Crystal structure of beta site APP cleaving enzyme (BACE) and methods of use thereof

ABSTRACT

The present application discloses and claims mutant BACE proteins, recombinant BACE proteins, processes for crystallizing BACE and in particular to its crystal structure and to the uses of this structure in drug discovery.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 60/398,681 filed Jul. 26, 2002, and corresponds to International Patent Application number ______ (Attorney docket number AHB/CP6162168) filed Jul. 25, 2003.

[0002] All documents cited in this text, and all documents cited or referenced in documents cited in this text, and any manufacturer's instructions or catalogues for any products cited or mentioned in this text or in any document hereby incorporated into this text, are hereby incorporated herein by reference. Documents incorporated by reference into this text or any teachings therein may be used in the practice of this invention. Documents incorporated by reference into this text are not admitted to be prior art. Furthermore, authors or inventors on documents incorporated by reference into this text are not to be considered to be “another” or “others” as to the present inventive entity and vice versa, especially where one or more authors or inventors on documents incorporated by reference into this text are an inventor or inventors named in the present inventive entity.

FIELD OF THE INVENTION

[0003] The present invention relates to the mutant BACE proteins, recombinant BACE proteins, processes for crystallizing BACE and in particular to its crystal structure and to the uses of this structure in drug discovery.

BACKGROUND TO THE INVENTION

[0004] Alzheimer's Disease

[0005] Alzheimer's disease (AD) is estimated to afflict more than 20 million people worldwide and is believed to be the most common form of dementia. Alzheimer's disease is a progressive dementia in which massive deposits of aggregated protein breakdown products—amyloid plaques and neurofibrillary tangles accumulate in the brain. The amyloid plaques are thought to be responsible for the mental decline seen in Alzheimer's patients.

[0006] Aβ or amyloid-β-protein is the major constituent of the plaques which are characteristic of Alzheimer's disease (De Strooper et al, 1999). Aβ is a 39-42 residue peptide formed by the specific cleavage of a class I transmembrane protein called APP, or amyloid precursor protein. A β-secretase activity cleaves this protein between residues Met671 and Asp672 (numbering of 770aa isoform of APP) to form the N-terminus of Aβ. A second cleavage of the peptide is associated with β-secretase to form the C-terminus of the Aβ peptide.

[0007] Beta Site APP Cleaving Enzyme (BACE) and Alzheimer's Disease

[0008] Several groups have identified and isolated aspartate proteases that have β-secretase activity (Hussain et al., 1999; Lin et. al, 2000; Yan et. al, 1999; Sinha et. al., 1999 and Vassar et. al., 1999). β-secretase is also known in the literature as Asp2 (Yan et. al, 1999), Beta site APP Cleaving Enzyme (BACE or BACE1 ) (Vassar et. al., 1999) or memapsin-2 (Lin et al., 2000). BACE was identified using a number of experimental approaches such as EST database analysis (Hussain et al. 1999); expression cloning (Vassar et al. 1999); identification of human homologs from public databases of predicted C. elegans proteins (Yan et al. 1999) and finally utilizing an inhibitor to purify the protein from human brain (Sinha et al. 1999). Thus, five groups employing three different experimental approaches led to the identification of the same enzyme, making a strong case that BACE is a β-secretase. Mention is also made of the patent literature: WO96/40885, EP871720, U.S. Pat. Nos. 5,942,400 and 5,744,346, EP855444, U.S. Pat. No. 6,319,689, WO99/64587, WO99/31236, EP1037977, WO00/17369, WO01/23533, WO0047618, WO00/58479, WO00/69262, WO01/00663, WO01/00665, U.S. Pat. No. 6,313,268.

[0009] BACE is a membrane bound type 1 protein that is synthesized as a partially active proenzyme, and is abundantly expressed in brain tissue. It is thought to represent the major β-secretase activity, and is considered to be the rate-limiting step in the production of Aβ. It is thus of special interest in the pathology of Alzheimer's disease, and in the development of drugs as a treatment for Alzheimer's disease.

[0010] BACE was found to be a pepsin-like aspartyl proteinase, the mature enzyme consisting of the N-terminal catalytic domain, a transmembrane domain, and a small cytoplasmic domain. BACE has an optimum activity at pH 4.0-5.0 (Vassar et al, 1999) and is inhibited weakly by standard pepsin inhibitors such as pepstatin. It has been shown that the catalytic domain minus the transmembrane and cytoplasmic domain has activity against substrate peptides (Lin et al, 2000). Consequently, this soluble catalytic domain is suitable for crystallization studies and a crystal structure of this will give a representative structure of the BACE active site for the design of inhibitor molecules.

[0011] The likelihood of developing Alzheimer's disease increases with age, and as the aging, population of the developed world increases, this disease becomes a greater and greater problem. In addition to this, there is a familial link to Alzheimer's disease and consequently any individuals possessing the double mutation of APP known as the Swedish mutation (in which the mutated APP forms a considerably improved substrate for BACE) have a much greater chance of developing AD, and also of developing it at an early age (see also U.S. Pat. Nos. 6,245,964 and 5,877,399 pertaining to transgenic rodents comprising APP-Swedish). Consequently there is a strong case for developing a compound that can be used in a prophylactic fashion for these individuals.

[0012] Hence, drugs that reduce or block BACE activity would reduce Aβ levels and levels of fragments of Aβ in the brain or elsewhere where Aβ or fragments thereof deposit and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of Aβ or fragments thereof (Yankner, 1996; De Strooper and Konig, 1999). BACE is therefore an important candidate for the development of drugs as a treatment against Alzheimer's disease and/or against such other maladies.

[0013] The therapeutic potential of inhibiting the deposition of Aβ has motivated many groups to isolate and characterize secretase enzymes and to identify their potential inhibitors (see, e.g., WO01/23533 A2, EP0855444, WO00/17369, WO00/58479, WO00/47618, WO00/77030, WO01/00665, WO01/00663, WO01/29563, WO002/25276, U.S. Pat No. 5,942,400, U.S. Pat. No. 6,245,884, U.S. Pat. No. 6,221,667, U.S. Pat. No. 6,211,235, WO02/02505, WO02/02506, WO02/02512, WO02/02518, WO02/02520, WO02/14264).

[0014] The gene encoding APP is found on chromosome 21, which is also the chromosome found as an extra copy in Downs syndrome. Downs syndrome patients tend to acquire Alzheimers disease at an early age, with almost all those over 40 years of age showing Alzheimers-type pathology (Oyama et al., 1994). This is thought to be due to the extra copy of the APP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of APPβ causing the high prevalence of Alzheimers disease seen in this population. Thus inhibitors of BACE could be useful in reducing Alzheimers-type pathology in Down's syndrome patients.

[0015] It would therefore be useful to inhibit the deposition of Aβ and portions thereof by inhibiting BACE through inhibitors designed from the BACE structure as provided herein. The determination of the three-dimensional structure of BACE provides a basis for the design of new and specific ligands for BACE. For example, knowing the three-dimensional structure of BACE, computer modelling programs may be used to design different molecules expected to interact with possible or confirmed binding cavities or other to structural or functional features of BACE or structure-based design approaches may used such as those described in Blundell et al (Nature Reviews, Drug Discovery, Vol 1, pg 45-54, 2002).

[0016] Ideally it would be desirable to have an abundant supply of this enzyme in homogenous form. It would also be preferable to solve the structure of a form of BACE with an unoccupied active site. This could be used to soak in small molecule inhibitors of the enzyme and to investigate their binding modes. We describe here the high yielding production of BACE from bacterial cells in homogenous form, and the generation of protein suitable for crystallisation and structure determination of BACE in Apo form

[0017] Protein Crystallisation

[0018] It is well known in the art of protein chemistry that crystallising a protein is an uncertain and difficult process without any clear expectation of success. It is now evident that protein crystallization is the main hurdle in protein structure determination. For this reason, protein crystallization has become a research subject in and of itself, and is not simply an extension of the protein crystallographer's laboratory. There are many references, which describe the difficulties associated with growing protein crystals (Kierzek A M. and Zielenkiewicz P. (2001) Biophysical Chemistry 91 1-20 Models of protein crystal growth, Wiencek J M (1999) Annu Rev Biomed Eng 1 505-534 New Strategies for crystal growth).

[0019] The reasons why it is commonly held that crystallization of protein molecules from solution is the major obstacle in the process of determining protein structures are many; proteins are complex molecules, and the delicate balance involving specific and non-specific interactions with other protein molecules and small molecules in solution, is difficult to predict.

[0020] Each protein crystallizes under a unique set of conditions, which cannot be predicted in advance. Simply supersaturating the protein to bring it out of solution will not work, the result would, in most cases, be an amorphous precipitate. Many precipitating agents are used, common ones are different salts, and polyethylene glycols, but others are known. In addition, additives such as metals and detergents can be added to modulate the behaviour of the protein in solution. Many kits are available (e.g., from Hampton Research), which attempt to cover as many parameters in crystallization space as possible, but in many cases these are just a starting point to optimize crystalline precipitates and crystals which are unsuitable for diffraction analysis. Successful crystallization is aided by knowledge of the proteins behaviour in terms of solubility, dependence on metal ions for correct folding or activity, interactions with other molecules and any other information that is available. Even so, crystallization of proteins is often regarded as a time-consuming process, whereby subsequent experiments build on observations of past trials.

[0021] In cases where protein crystals are obtained, these are not necessarily always suitable for diffraction analysis; they may be limited in resolution, and it may subsequently be difficult to improve them to the point at which they will diffract to the resolution required for analysis. Limited resolution in a crystal can be due to several things. It may be due to intrinsic mobility of the protein within the crystal; this can be difficult to overcome, even with other crystal forms. It may be due to high solvent content within the crystal, which consequently results in weak scattering. Alternatively, it could be due to defects within the crystal lattice, which means that the diffracted x-rays will not be completely in phase from unit to unit within the lattice. Any one of these or a combination of these could mean that the crystals are not suitable for structure determination.

[0022] Some proteins never crystallize, and after a reasonable attempt it is necessary to examine the protein itself and consider whether it is possible to make individual domains, different N or C-terminal truncations, or point mutations. It is often hard to predict how a protein could be re-engineered in such a manner as to improve crystallisability. Sometimes the inclusion of a ligand in the crystallisation mixture is essential for the production suitable crystals. Our understanding of crystallisation mechanisms is still incomplete and the factors of protein structure, which are involved in crystallisation, are not well known.

[0023] BACE Production for Crystallisation

[0024] Beta secretase (BACE) is an integral membrane protein containing a signal sequence, a pro-peptide, a catalytic aspartyl protease domain, a transmembrane region and a C-terminal cytoplasmic region. During transit through the endoplasmic reticulum, Golgi apparatus and trans Golgi network the pro-peptide is cleaved by a furin-like protease (Bennett et al 2000, Creemers et al 2001) and N-glycosylation is added and matured (Haniu et al 2000). The protein contains 4 potential N-linked glycosylation sites, all of which are used (Bennett et al, 2000).

[0025] Certain active recombinant BACEs—different from those of the herein invention—have been produced using heterologous expression systems for mammalian cells (Vassar et al, 1999, Hussain et al, 1999), insect cells (Mallender et al, 2000) and bacterial cells (Lin et al 2000). Preferred constructs for crystallisation would be soluble and lack glycosylation: the former can be achieved by C-terminal truncation of the protein to remove the transmembrane and cytoplasmic regions; while glycosylation could be removed either by use of a deglycosylating agent such as PNGase F, by expression of the protein in bacteria or by mutation of the glycosylation sites.

[0026] The protein used for BACE crystallisation by Hong et al (2000) was produced in bacteria and was truncated at the C-terminus. Their protein was produced as insoluble inclusion bodies and required refolding to give soluble, active protein. Refolding of BACE is made more complex by the presence of 3 disulphide bonds in the native protease domain, which require careful control of redox conditions to form during in-vitro refolding. The protein produced by Hong et al was a mixture of products and was crystallised with inhibitor bound (see WO 01/00663, WO 01/00665, and U.S. Pat. No. 6,545,127).

[0027] Mention is also made of WO 02/25276, which describes the crystallisation of BACE produced in mammalian cells. The protein produced also was a mixture of protein species and was also crystallized with an inhibitor bound.

[0028] Mention is also made of WO03/012089, which describes the crystallisation of BACE produced from insect cells. The co-ordinates of BACE with an inhibitor bound are provided.

SUMMARY OF THE INVENTION

[0029] In general aspects, the present invention is concerned with the provision of a new, high resolution, apo, crystal form of BACE and the use of this structure in identifying or obtaining agent compounds (especially inhibitors of BACE) for modulating BACE activity, and in preferred embodiments identifying or obtaining actual agent compounds/inhibitors. Crystal structure information presented herein is useful in designing potential inhibitors and modelling them or their potential interaction with the BACE binding cavity. Potential inhibitors may be brought into contact with BACE to test for ability to interact with the BACE binding cavity. Actual inhibitors may be identified from among potential inhibitors synthesized following design and model work performed in silico. An inhibitor identified using the present invention may be formulated into a composition, for instance a composition comprising a pharmaceutically acceptable excipient, and may be used in the manufacture of a medicament for use in a method of treatment.

[0030] Thus, according to a first aspect of the present invention there is provided a mutant BACE protein, which protein lacks one or more proteolytic cleavage sites recognized by clostripain (or another protease which recognizes the same cleavage site as clostripain). In particular, the protein is a BACE protein, which comprises the sequence set out in residues 45 to 455 of SEQ ID NO:2 (43 to 453 SwissProt P56817), or a fragment thereof comprising residues corresponding to 58 to 398 of SEQ ID NO:2, modified by the following changes: (a) substitution or deletion of at least one residue which is a proteolytic cleavage site recognised by clostripain; and (b) optionally the replacement of from 1 to 30 other amino 25 acids by an equivalent or fewer number of amino acids. It will be understood that when the BACE protein comprises a fragment as defined above, the fragment will comprise at least feature (a) and optionally feature (b).

[0031] The modification is such that the BACE protein preferably retains at least one proteolytic cleavage site recognised by clostripain so that it may be cleaved to provide homogeneous location at which cleavage occurs.

[0032] According to a second aspect of the present invention there is provided a mutant BACE protein which is truncated at the N-terminal up to and including R42, R45, G55, R56 or R57. In a preferred aspect, when the protein is truncated up and including R56 the residue at position 57 is not arginine. It may for example be lysine.

[0033] In a third aspect the invention provides a mutant BACE protein selected from: (a) SEQ ID 6; (b) SEQ ID 8; (c) SEQ ID 10; (d) SEQ ID 12; (e) SEQ ID 14; (f) SEQ ID 16; (g) SEQ ID 18; (h) SEQ ID 19; (i) SEQ ID 20; (j) SEQ ID 21.

[0034] In another aspect, the invention contemplates a nucleic acid (e.g. DNA or RNA) sequence encoding the BACE protein of the invention, as well as the complementary nucleic acid sequence counterpart.

[0035] The nucleic acids of the invention may be isolated, or may be present in the context of a vector or host cell. Thus, in another aspect, the invention contemplates a vector comprising the nucleic acid of the invention.

[0036] The nature of the vector of the invention is not critical to the invention. Any suitable vector may be used, including expression vectors, plasmid, virus, bacteriophage, transposon, minichromosome, liposome or mechanical carrier.

[0037] The expression vectors of the invention are DNA constructs suitable for expressing DNA which encodes the desired peptide and which may include: (a) a regulatory element (e.g. a promoter, operator, activator, repressor and/or enhancer), (b) a structural or coding sequence which is transcribed into mRNA and (c) appropriate transcription, translation, initiation and termination sequences. They may also contain sequence encoding any of various tags (e.g. to facilitate subsequent purification of the expressed protein, such as affinity (e.g. His tags).

[0038] Particularly preferred are vectors which comprise an expression element or elements operably linked to the DNA of the invention to provide for expression thereof at suitable levels. Any of a wide variety of expression elements may be used, and the expression element or elements may for example be selected from promoters, enhancers, ribosome binding sites, operators and activating sequences. Such expression elements may comprise an enhancer, and for example may be regulatable, for example being inducible (via the addition of an inducer).

[0039] The vector may further comprise a positive selectable marker and/or a negative selectable marker. The use of a positive selectable marker facilitates the selection and/or identification of cells containing the vector.

[0040] In another aspect, the invention contemplates a host cell comprising the vector of the invention. The nucleic acid of the invention may be intrdoduced into the host cell by any of a large number of convenient methods, including calcium phosphate transfection, DEAE-Dextran mediated transfection, electroporation or any other method known in the art.

[0041] Any suitable host cell may be used, including prokaryotic host cells (such as Escherichia, coli, Streptomyces spp. and Bacillus subtilis) and eukaryotic host cells. Suitable eukaryotic host cells include insect cells (e.g. using the baculovirus expression system), mammalian cells, fungal (e.g. yeast) cells and plant cells. Preferred mammalian cells are animal cells such as CHO, COS, C 127, 3T3, HeLa, HEK 293, NIH 3T3, BHK and Bowes melanoma (particularly preferred being CHO-K1, COS7, Y1 adrenal and carcinoma cells).

[0042] Cell-free translation systems can also be used to produce the peptides of the invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y., (1989).

[0043] Prokaryotic host cells are preferred in circumstances where the BACE protein is required in an unglycosylated state.

[0044] According to another aspect of the invention there is provided a process for producing the BACE protein of the invention comprising the steps of: (a) culturing the host cell of the invention under conditions suitable for expression of the BACE protein; and optionally (b) isolating the expressed recombinant BACE protein.

[0045] In a further aspect the invention provides a method of making BACE protein which comprises protedlytically cleaving a BACE protein which lacks one of more proteolytic cleavage sites as described above, the cleavage desirably occurring at (and including) one of position 42, 45, 55, 56 or 57, preferably 42, 56 or 57. Clostripain, or another protease which recognises the same cleavage site as clostripain, may be used.

[0046] Thus the resulting BACE protein of this aspect of invention will be a protein whose N-terminal corresponds to 45, 48, 58, 59 or 60 of SEQ ID NO:2, and whose C-terminal region extends to and includes at least 398 of SEQ ID NO:2. Preferably the C-terminal region terminates at a residue between a point corresponding to and including 398 up to and including 455. This BACE protein may additionally comprise a C-terminal tag, such as a tag comprising from 5 to 15 residues, such as a his tag or the like.

[0047] In another aspect of the invention there is provided a process for producing refolded recombinant BACE protein comprising the steps of: (a) solubilising the recombinant BACE; (b) diluting the solubilised BACE into an aqueous buffer containing sulfobetaine (for example at a concentration of 10 to 50 mM, for example 10 mM); and (c) maintaining the diluted solution at low temperature (for example, 3 to 6° C.) and at high pH (e.g. 9 to 10.5) for at least 2 weeks (typically 3 weeks, more typically 4 weeks).

[0048] In another aspect the invention provides a process for producing a crystal of BACE comprising the step of growing the crystal by vapour diffusion using a reservoir buffer that contains 18-26% PEG 5000 MME (for example, 20-24% PEG 5000 MME, e.g. 20-22.5% PEG 5000 MME), 180-220 mM (e.g. 200 mM) ammonium iodide and 180-22-mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6). In a further aspect the reservoir buffer may additionally comprise from 0 to 5% (v/v) glycerol, for example 2.5% v/v.

[0049] In another aspect the invention provides various BACE crystals, including a crystal of BACE having a hexagonal space group P6₂₂ (and optionally having unit cell dimensions of a=b=103.2 Å, c=169.1 Å,α=β=60°, γ=120 °, and a unit cell variability of 5% in all dimensions); a crystal of BACE having a resolution better than 3 Å (for example, better than 2.5 Å, e.g. better than 1.8 Å), and a crystal of BACE comprising a structure defined by all or a portion of the co-ordinates of Table 1.

[0050] In another aspect the invention provides a three-dimensional representation of BACE or of a portion of BACE, which representation comprises all or a portion of the coordinates of Table 1. The representation is preferably a BACE model.

[0051] The invention also contemplates a three-dimensional representation of a compound which fits the BACE model of the invention.

[0052] The invention also contemplates a computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing a BACE model; (b) providing a molecular structure to be fitted to said BACE model; and (c) fitting the molecular structure to the BACE model to produce a compound model.

[0053] In another aspect the invention provides a computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing the structure of a BACE as defined by the coordinates of Table 1; (b) providing a molecular structure to be fitted to said BACE structure; and (c) fitting the molecular structure to the BACE structure of Table 1.

[0054] In another aspect the invention provides a computer-based method for the analysis of molecular structures which comprises: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structure of a molecular structure to be fitted to the selected coordinates; and (c) fitting the structure to the selected coordinates of the BACE structure.

[0055] In another aspect the invention provides a computer-based method of rational drug design comprising comprising: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structures of a plurality of molecular fragments; (c) fitting the structure of each of the molecular fragments to the selected coordinates; and (d) assembling the molecular fragments into a single molecule to form a candidate modulator molecule.

[0056] In another aspect the invention provides a method for identifying a candidate modulator (e.g. candidate inhibitor) of BACE comprising the steps of: (a) employing a three-dimensional structure of BACE, at least one sub-domain thereof, or a plurality of atoms thereof, to characterise at least one BACE binding cavity, the three-dimensional structure being defined by atomic coordinate data according to Table 1; and (b) identifying the candidate modulator by designing or selecting a compound for interaction with the binding cavity.

[0057] In another aspect the invention provides a method for identifying an agent compound (e.g. an inhibitor) which modulates BACE activity, comprising the steps of: (a) employing three-dimensional atomic coordinate data according to Table 1 to characterise at least one (e.g. a plurality of) BACE binding site(s); (b) providing the structure of a candidate agent compound; (c) fitting the candidate agent compound to the binding sites; and (d) selecting the candidate agent compound.

[0058] In another aspect the invention provides a method of assessing the ability of a candidate modulator to interact with BACE which comprises the steps of: (a) obtaining or synthesising said candidate modulator; (b) forming a crystallized complex of BACE and said candidate modulator; and (c) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said candidate modulator to interact with BACE.

[0059] In another aspect the invention provides a method for determining the structure of a compound bound to BACE, said method comprising: (a) mixing BACE with the compound to form a BACE-compound complex; (b) crystallizing the BACE-compound complex; and (c) determining the structure of said BACE-compound(s) complex by reference to the data of Table 1.

[0060] In another aspect the invention provides a method for determining the structure of a compound bound to BACE, said method comprising: (a) providing a crystal of BACE; (b) soaking the crystal with one or more compound(s) to form a complex; and (c) determining the structure of the complex by employing the data of Table 1.

[0061] In another aspect the invention provides a method of determining the three dimensional structure of a BACE homologue or analogue of unknown structure, the method comprising the steps of: (a) aligning a representation of an amino acid sequence of the BACE homologue or analogue with the amino acid sequence of the BACE of Table 1 to match homologous regions of the amino acid sequences; (b) modelling the structure of the matched homologous regions of said target BACE of unknown structure on the corresponding regions of the BACE structure as defined by Table 1; and (c) determining a conformation for the BACE homologue or analogue which substantially preserves the structure of said matched homologous regions.

[0062] In another aspect the invention provides a method of providing data for generating structures and/or performing rational drug design for BACE, BACE homologues or analogues, complexes of BACE with a potential modulator, or complexes of BACE homologues or analogues with potential modulators, the method comprising: (i) establishing communication with a remote device containing computer-readable data comprising at least one of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE, at least one sub-domain of the three-dimensional structure of BACE, or the coordinates of a plurality of atoms of BACE; (b) structure factor data for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE homologue or analogue generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d); and (ii) receiving said computer-readable data from said remote device.

[0063] In another aspect the invention provides a computer system containing one or more of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE or at least selected coordinates thereof; (b) structure factor data (where a structure factor comprises the amplitude and phase of the diffracted wave) for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a target BACE protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; or (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0064] In another aspect the invention provides a computer-readable storage medium, comprising a data storage material encoded with computer readable data, wherein the data are defined by all or a portion of the structure coordinates of BACE of Table 1, or a homologue of BACE, wherein said homologue comprises backbone atoms that have a root mean square deviation from the Cα or backbone atoms (nitrogen-carbon_(α)-carbon) of Table 1 of less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å when superimposed on the coordinates provided in Table 1 for the residue backbone atoms.

[0065] In another aspect the invention provides a computer-readable data storage medium comprising a data storage material encoded with a first set of computer-readable data comprising a Fourier transform of at least a portion (e.g. selected coordinates as defined herein) of the structural coordinates for BACE according to Table 1; which, when combined with a second set of machine readable data comprising an X-ray diffraction pattern of a molecule or molecular complex of unknown structure, using a machine programmed with the instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data.

[0066] In another aspect the invention provides a computer readable medium with at least one of: (a) atomic coordinate data according to Table 1 recorded thereon, said data defining the three-dimensional structure of BACE, or at least selected coordinates thereof; (b) structure factor data for BACE recorded thereon, the structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a BACE-ligand complex or a BACE homologue or analogue generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0067] In another aspect the invention provides a method for determining the structure of a protein, which method comprises; providing the co-ordinates of Table 1, and either (a) positioning the co-ordinates in the crystal unit cell of said protein so as to provide a structure for said protein or (b) assigning NMR spectra Peaks of said protein by manipulating the coordinates of Table 1.

[0068] In another aspect the invention contemplates BACE modulator molecules, medicaments, pharmaceutical compositions and drugs obtainable by, or obtained by, the processes and methods of the invention, and to methods of therapy (e.g. the treatment of Alzheimer's disease) using such products.

[0069] It is to be understood that, except where explicitly stated otherwise, references herein to “BACE protein” or “BACE peptide”, “mutant BACE protein” or “mutant BACE peptide” and to “BACE protein” or “BACE peptide”, as well as references to any of the foregoing which are further defined inter alia by reference to one or more specific amino acid sequences, are intended to cover BACE homologues, allelic forms, species variants, derivatives and muteins thereof (as defined below).

[0070] Thus, references to mutant BACE proteins having particular amino acid sequences may optionally be interpreted to cover the corresponding homologues, allelic forms, species variants, derivatives and muteins (as defined below) of that particular BACE amino acid sequence.

DEFINITIONS

[0071] Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

[0072] The term “isolated” is used herein to indicate that the isolated moiety (e.g. peptide or nucleic acid) exists in a physical milieu distinct from that in which it occurs in nature. For example, the isolated peptide may be substantially isolated with respect to the complex cellular milieu in which it naturally occurs. The absolute level of purity is not critical, and those skilled in the art can readily determine appropriate levels of purity according to the use to which the peptide is to be put. The term “isolating” when used a step in a process is to be interpreted accordingly.

[0073] In many circumstances, the isolated moiety will form part of a composition (for example a more or less crude extract containing many other molecules and substances), buffer system, matrix or excipient, which may for example contain other components (including proteins, such as albumin).

[0074] In other circumstances, the isolated moiety may be purified to essential homogeneity, for example as determined by PAGE or column chromatography (for example HPLC or mass spectrometry). In preferred embodiments, the isolated peptide or nucleic acid of the invention is essentially the sole peptide or nucleic acid in a given composition.

[0075] The proteins and nucleic acids of the invention need not be isolated in the sense defined above, however. For example, more or less crude culture supernatants (e.g. “spent” medium) may contain sufficient concentrations of the proteins or nucleic acids of the invention for use in several applications. Preferably, such supernatants are fractionated and/or extracted, but in many circumstances they may be used without pretreatment. They are preferably derived from spent media used to culture the host cells of the invention (for example, the bacterial sources described infra). The supernatants are preferably sterile. They may be treated in various ways, for example by concentration, filtration, centrifugation, spray drying, dialysis and/or lyophilisation. Conveniently, the culture supernatants are simply centrifuged to remove cells/cell debris and filtered.

[0076] The term “pharmaceutical composition” is used herein to define a solid or liquid composition in a form, concentration and level of purity suitable for administration to a patient (e.g. a human or animal patient) upon which administration it can elicit the desired physiological changes.

[0077] The term “recombinant” as applied to the proteins of the invention is used herein to define a protein that has been produced by that body of techniques collectively known as “recombinant DNA technology” (for example, using the nucleic acid, vectors and or host cells described herein).

[0078] The term “synthetic” as applied to the peptides of the invention is used herein to define a peptide that has been chemically synthesised in vitro (for example by any of the commercially available solid-phase peptide-synthesis systems).

[0079] As used herein in relation to the vectors of the invention, the term “operably linked” refers to a condition in which portions of a linear nucleic acid sequence are capable of influencing the activity of other portions of the same linear nucleic acid sequence. For example, DNA for a signal peptide (secretory leader) is operably linked to DNA for a polypeptide if it is expressed as a precursor which participates in the secretion of the polypeptide; a promoter is operably linked to a coding sequence if it controls the transcription of the sequence; a ribosome binding site is operably linked to a coding sequence if it is positioned in the correct reading-frame so as to permit translation.

[0080] By “apo-structure” we mean the three-dimensional structure of the protein that contains no ligand, e.g. substrate or product or cofactor or inhibitor i.e. the active site of the protein is empty.

[0081] In the following by “binding site” or “binding cavity” we mean a site (such as an atom, a functional group of an amino acid residue or a plurality of such atoms and/or groups) in a BACE binding cavity, which may bind to an agent compound such as a candidate inhibitor. Depending on the particular molecule in the cavity, sites may exhibit attractive or repulsive binding interactions, brought about by charge, steric considerations and the like.

[0082] Binding sites are sites within a macromolecule, or on its surface, at which ligands can bind. Examples are the catalytic or active site of an enzyme (the site on an enzyme at which the amino acid residues involved in catalysing the enzymatic reaction are located), allosteric binding sites (ligand binding sites distinct from the catalytic site, but which can modulate enzymatic activity upon ligand binding), cofactor binding sites (sites involved in binding/co-ordinating cofactors e.g. metal ions), or substrate binding sites (the ligand binding sites on a protein at which the substrates for the enzymatic reaction bind). There are also sites of protein-protein interaction.

[0083] In the following by “active site” we mean a site (such as an atom, a functional group of an amino acid residue or a plurality of such atoms and/or groups) in a BACE binding cavity, which is involved in catalysis.

[0084] By “fitting”, is meant determining by automatic, or semi-automatic means, interactions between one or more atoms of a candidate molecule and at least one atom of a BACE structure of the invention, and calculating the extent to which such interactions are stable. Interactions include attraction and repulsion, brought about by charge, steric considerations and the like. Various computer-based methods for fitting are described further herein.

[0085] By “root mean square deviation” we mean the square root of the arithmetic mean of the squares of the deviations from the mean.

[0086] By a “computer system” we mean the hardware means, software means and data storage means used to analyse atomic coordinate data. The minimum hardware means of the computer-based systems of the present invention typically comprises a central processing unit (CPU), input means, output means and data storage means. Desirably a monitor is provided to visualise structure data. The data storage means may be RAM or means for accessing computer readable media of the invention. Examples of such systems are microcomputer workstations available from Silicon Graphics Incorporated and Sun Microsystems running Unix based, Windows NT or IBM OS/2 operating systems.

[0087] By “computer readable media” we mean any medium or media, which can be read and accessed directly by a computer e.g. so that the media is suitable for use in the above-mentioned computer system. Such media include, but are not limited to: magnetic storage media such as floppy discs, hard disc storage medium and magnetic tape; optical storage media such as optical discs or CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.

[0088] The term “homologue” is used herein in two distinct senses. It is used sensu stricto to define proteins that share a common ancestor. In this sense it covers orthologues (species variants which have diverged in different organisms following a speciation event) and paralogues (variants which have diverged within the same organism after a gene duplication event). Thus, there is a direct evolutionary relationship between such homologues and this may be reflected in structural and/or functional similarities. For example, orthologues may perform the same role in each organism in which they are found, while paralogues may perform functionally related (but distinct) roles within the same organism.

[0089] The term is also used herein sensu lato to define proteins which are to some extent structurally similar (i.e. not necessarily evolutionary related and/or structurally and functionally equivalent). In this sense, homology is recognised on the basis of purely structural criteria by the presence of amino acid sequence identities and/or conservative amino acid changes and/or similar secondary, tertiary or quaternary structures.

[0090] The term “analogue” is used herein to define proteins with similar functions and/or structures and which are not necessarily evolutionary related. Protein analogues which share function but which have no or little structural similarities are likely to have arisen by convergent evolution. Conversely, protein analogues which share structural similarities but which exhibit few or no functional similarities are likely to have arisen by divergent evolution. Protein analogues may be identified, for example, by screening a library of proteins to detect those with similar function(s) but different physical properties, or by screening for proteins which share structural features but not necessarily any functions (e.g. by immunological screening).

[0091] The term “equivalent” is used herein to define those protein analogues which exhibit substantially the same function(s) and which share at least some structural features (e.g. functional domains), but which have not evolved from a common ancestor. Such equivalents are typically synthetic proteins (see below) and may be generated, for example, by identifying sequences of functional importance (e.g. by identifying conserved or canonical sequences, functional domains or by mutagenesis followed by functional assay), selecting an amino acid sequence on that basis and then synthesising a peptide based on the selected amino acid sequence. Such synthesis can be achieved by any of many different methods known in the art, including solid phase peptide synthesis (to generate synthetic peptides) and the assembly (and subsequent cloning) of oligonucleotides. Some synthetic protein analogues may be chimaeras (see below), and such equivalents can be designed and assembled for example by concatenation of two or more different structural and/or functional peptide domains from different proteins using recombinant DNA techniques (see below).

[0092] The BACE protein homologues of the invention therefore include proteins and peptides having at least 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% sequence identity with the reference protein, and include truncated forms of the BACE proteins of the invention. Such truncates are preferably at least 25%, 35%, 50% or 75% of the length of the corresponding specifically exemplified proteins and may have at least 60% sequence identity (more preferably, at least 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% sequence identity) with that specifically exemplified protein.

[0093] Particularly preferred homologues are truncates that contain a segment preferably comprising at least 8, 15, 20 or 30 contiguous amino acids that share at least 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% sequence identity with that specifically exemplified protein.

[0094] A “conservative amino acid change” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g. lysine, arginine and histidine), acidic side chains (e.g. aspartic acid and glutamic acid), non-charged polar side chains (e.g. glycine, asparagine, glutamine, serine, threonine, tyrosine and cysteine), non-polar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan), beta-branched side chains (e.g. threonine, valine and isoleucine), and aromatic side chains (e.g. tyrosine, phenylalanine, tryptophan and histidine).

[0095] Thus, references herein to proteins and peptides that are to some defined extent “identical” (or which share a defined extent of “identity”) with a reference protein or peptide may also optionally be interpreted to include proteins and peptides in which conservative amino acid changes are disregarded so that the original amino acid and its changed counterpart are regarded as identical for the purposes of sequence comparisons.

[0096] The term “allelic form” is used herein to define a naturally-occurring alternative forms of the sequence present in the BACE protein which reflect naturally-occurring differences in the BACE gene pool. Preferably, allelic variants of the proteins of the invention have at least 60% sequence identity (more preferably, at least 75%, 80%, 85%, 90% or 95% sequence identity) with the corresponding specifically exemplified BACE protein, where sequence identity is determined by comparing the nucleotide sequences of the polynucleotides when aligned so as to maximize overlap and identity while minimizing sequence gaps.

[0097] The term “species variant” (or orthologue) is used herein to define the corresponding protein from a different organism. Thus, species variants share a direct evolutionary relationship.

[0098] The term “derivative” as applied herein to the BACE proteins of the invention is used to define proteins which are modified versions of the specifically exemplified proteins of the invention. Such derivatives may include fusion proteins, in which the proteins of the invention have been fused to one or more different proteins, peptides or amino acid tags (for example an antibody or a protein domain conferring a biochemical activity, to act as a label, or to facilitate purification). Particularly preferred are derivatives in which the peptides are modified by a polyHis (6×His) tag to facilitate purification of the peptide derivative on Ni²⁺ agarose beads.

[0099] The derivatives may also be products of synthetic processes that use a peptide of the invention as a starting material or reactant.

[0100] The term “mutein” is used herein to define proteins that are mutant forms of the BACE proteins of the invention, i.e. proteins in which one or more amino acids have been added, altered, deleted, replaced, inserted or substituted. Thus, the terms “BACE mutein” and “mutant BACE protein” are used interchangeably herein. The muteins/mutant BACE proteins of the invention therefore include fragments, truncates and fusion proteins and peptides (e.g. comprising fused immunoglobulin, receptor, tag, label or enzyme moieties).

[0101] The muteins of the invention therefore include truncated forms of the BACE proteins of the invention. Such truncates are preferably least 25%, 35%, 50% or 75% of the length of the corresponding specifically exemplified BACE protein and may have at least 60% sequence identity (more preferably, at least 75%, 80%, 85%, 90% or 95% sequence identity) with that specifically exemplified protein.

[0102] Particularly preferred are truncates that contain a segment preferably comprising at least 8, 15, 20 or 30 contiguous amino acids that share at least 75%, 80%, 85%, 90% or 95% sequence identity with that specifically exemplified protein.

[0103] For the purposes of the present invention, sequence identity is determined by comparing the amino acid sequences of the proteins when aligned so as to maximize overlap and identity while minimizing sequence gaps. In particular, sequence identity may be determined using any of a number of mathematical algorithms. A nonlimiting example of a mathematical algorithm used for comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87: 2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90: 5873-5877.

[0104] Another example of a mathematical algorithm used for comparison of sequences is the algorithm of Myers and Miller (1988) CABIOS 4: 11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Yet another useful algorithm for identifying regions of local sequence similarity and alignment is the FASTA algorithm as described in Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444-2448.

[0105] Preferred for use according to the present invention is the WU-BLAST (Washington University BLAST) version 2.0 software. WU-BLAST version 2.0 executable programs for several UNIX platforms can be downloaded from ftp://blast.wustl.edu/blast/executables. This program is based on WU-BLAST version 1.4, which in turn is based on the public domain NCBI-BLAST version 1.4 (Altschul and Gish, 1996, Local alignment statistics, Doolittle ed., Methods in Enzymology 266: 460-480; Altschul et al., 1990, Basic local alignment search tool, Journal of Molecular Biology 215: 403-410; Gish and States, 1993, Identification of protein coding regions by database similarity search, Nature Genetics 3: 266-272; Karlin and Altschul, 1993, Applications and statistics for multiple high-scoring segments in molecular sequences, Proc. Natl. Acad. Sci. USA 90: 5873-5877; all of which are incorporated by reference herein).

[0106] In all search programs in the suite the gapped alignment routines are integral to the database search itself. Gapping can be turned off if desired. The default penalty (Q) for a gap of length one is Q=9 for proteins and BLASTP, and Q=10 for BLASTN, but may be changed to any integer. The default per-residue penalty for extending a gap (R) is R=2 for proteins and BLASTP, and R=10 for BLASTN, but may be changed to any integer. Any combination of values for Q and R can be used in order to align sequences so as to maximize overlap and identity while minimizing sequence gaps. The default amino acid comparison matrix is BLOSUM62, but other amino acid comparison matrices such as PAM can be utilized.

[0107] The muteins of the invention also include peptides in which mutations have been introduced which effectively promote or impair one or more activities of the protein, for example mutations which promote or impair the function of a receptor, a recognition sequence or an effector binding site.

[0108] Muteins may be produced by any convenient method. Conveniently, site-directed mutagenesis with mutagenic oligonucleotides may be employed using a double stranded template (pBluescript KS II construct containing nucleic acid encoding the BACE protein), (e.g. Chameleon™ or QuikChange™-Stratagene™) or cassette mutagenesis methods my be employed. After verifying each mutant derivative by sequencing, the mutated gene is excised and inserted into a suitable vector so that the modified protein can be over-expressed and purified.

BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Table 1, provides the coordinates of the BACE structure. The numbering of the residues used in this Table (see Section (D) below) correspond to the numbering of used by Hong et al, ibid. Elsewhere—unless indicated to the contrary—in the specification the numbering of the SwissProt database entry P56817 is used. Residue 1 of Table 1 corresponds to 62 of SwissProt P56817, and residue 385 corresponds to 446 of SwissProt P56817. In the sequence listing below, the SwissProt P56817 residues 14-453 are shown as 16-455 of SEQ ID NO:2.

[0110]FIG. 1 represents the packing arrangements of the BACE monomers within the P6₁,22 crystal lattice.

[0111]FIG. 2 shows the superposition of BACE in complex with OM99-2 (1FKN), in black, with BACE, of the invention, in the absence of ligand (grey). The position of OM99-2 is defined by a stick representation of the inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

[0112] A. Construct Design

[0113] BACE protease is expressed, at high levels, as insoluble inclusion bodies in bacterial cells. To prepare functional protein appropriate for enzyme assay and structural studies these inclusion bodies are solubilised using denaturants and the slow removal of these denaturants results in the formation of the correct tertiary structure. In addition BACE is expressed as a pro-sequence and requires activation by a protease before it is fully functional.

[0114] One of the problems of the techniques described in the art (Tang et al) for isolation of BACE from inclusion bodies is the generation of a mixture of products from the uncontrolled cleavage process. Choppa et al describe the isolation of BACE from mammalian cells and the subsequent cleavage with protease, which also gives a mixture of protein species. Thus there is a need in the art for a method of generating active BACE as a homogenous species.

[0115] A further problem with the prior art techniques is the low yield of crystallisable material obtained. The inventors surprisingly found that the present invention results in a high yield from bacterial cells, in particular E. coli.

[0116] The inventors utilized clostripain as an activating protease to perform this cleavage in a controlled manner but this produced multiple species of BACE, as determined by mass spectrometry. In order to obtain a uniform homogenous protein after activation, a number of different constructs were produced. These constructs focused on the mutation of two of the clostripain cleavage sites (R56 and R57).

[0117] The sequences of the invention were designed to achieve a single cleavage point upon activation by clostripain, as activation of wild type sequence in this way resulted in a non-crystallisable protein with heterogeneous N termini.

[0118] The BACE constructs of the invention contain successful modifications of the BACE sequence to allow generation of homogeneous protein product from the use of clostripain. The sequence of the invention contains substitution for another amino acid residue or deletion of the arginine 56 and/or arginine 57 (numbering based on wild type full length sequence, SWISS_PROT P56817). In a preferred aspect of the invention this is a conserved substitution. Conservative amino acid substitutions are well known in the art, and include substitutions made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the amino acid residues involved. For example, positively charged amino acids include lysine and arginine and histidine. In a preferred aspect the mutation introduced is substitution of arginine to lysine at position 56 and/or 57, more preferably 56 and 57. This results in, as oppose to the wild type, the production of a single species of activated protein upon limited digest with clostripain. Clostripain cleavage occurs at a single site and is thus specific and generates a single species in minutes.

[0119] The advantage of these mutations is that they allow the controlled cleavage at arginine residue 42 and hence provides a single N-terminus.

[0120] This controlled cleavage thus provides a means to produce a substantially homogeneous composition of a BACE protein of the invention. By substantially homogeneous, it is meant that at least 95%, preferably at least 98% and more preferably at least 99% of the BACE protein in the composition has the same N-terminus. The N-terminus may be selected from residues 43 (i.e. by cleavage at 42), 46, 56, 57 or 58, preferably from 43, 56, 57 or 58, more preferably 43, 56 or 57.

[0121] These mutations can be introduced onto any sequence of BACE by site-directed mutagenesis techniques, to facilitate the generation of homogeneous material for structural or activity studies. Thus proteins of the invention are BACE proteins with residues 56 and/or 57 either mutated or deleted. Proteins of the invention also include BACE mutants described below in section (C).

[0122] The invention is exemplified by several constructs (SEQ ID 5-18). These were built based 15 on the wild type sequence (BACE WT, SEQ ID 2) where R56 and/or R57 were mutated to K or deleted. These were BACE WT R56KR57K (SEQ ID 6), BACE WT R57K (SEQ ID 8), BACE WT R57del (SEQ ID 10). This was also performed on the BACE construct BACE N->Q to give BACE N->Q R56KR57K (SEQ ID 12), BACE N->Q R57K (SEQ ID 16), BACE N->Q R57del (SEQ ID 18). The BACE N->Q construct contains 4 additional mutations of asparagines to glutamine and a C-terminal His tag as well as the arginine mutations. BACE N->Q without the His tag was mutated at 56 and 57 to give BACE N->Q R56K R57K no His (SEQ ID 14).

[0123] SEQ ID 19 is the activated from of SEQ ID 6, SEQ ID 21 the activated form of SEQ ID 12 and SEQ ID 20 the activated form of SEQ ID 14, i.e. the form in which the protein is crystallized:

[0124] The three BACE constructs BACE WT R56KR57K, BACE N->Q R56KR57K, and BACE N->Q R56KR57K no His gave higher expression levels.

[0125] Thus the invention concerns any BACE proteins with one or more of: a mutation at 56, and mutation at 57, or a deletion at 56 or a deletion at 57, but preferably 56 and 57 mutated, and crystals thereof i.e. any BACE protein comprising residues 56-396 of BACE (based on numbering of SwissProt P56817) and containing these mutations.

[0126] B. Refolding Protocol

[0127] The protein was expressed in E. coli as inclusion bodies, as outlined above. In an improvement of existing techniques BACE isolated from inclusion bodies was refolded by the use of high pH, a sulfobetaine refolding agent, and a longer duration at high pH. This refolding protocol increased the yield of refolded protein obtained and also gave high and reproducible yields of refolded BACE suitable for crystallisation.

[0128] The use of high pH in refolding (Burton et el, 1989) and of sulfobetaines as solubilising molecules in folding experiments (Goldberg et al, 1996) has previously been described. Here we describe the use of a combination of these technologies to give an unprecedented high yield of BACE. In addition to this combination of high pH and sulfobetaine, in another deviation from existing protocols for refolding BACE, the pH is maintained at high pH for at least 2 weeks. This is in comparison to the method of Tang et al, where BACE is solubilised at high pH and then the pH lowered before protein recovery at least 2-3 weeks later, preferably 3-4 weeks later.

[0129] Another aspect of the invention therefore concerns a novel method of producing soluble BACE proteins of the invention, utilizing a refolding protocol comprising the combined techniques of high pH buffer and the use of sulfobetaine, and also maintaining this high pH over at least two weeks.

[0130] More specifically, a method for producing refolded recombinant BACE comprising refolding the BACE under conditions which denature and then slowly renature the enzyme into a soluble form wherein: (a) the BACE is solubilised using a chaotrope such as urea or guanidine at 8-10M (typically 8 M urea solution) including one or more reducing agents at a pH of greater than 8.0 e.g. pH 9.0-10.5; (b) the BACE is then diluted into an aqueous buffer, like 20 mM-Tris, pH 9.0, containing sulfobetaine, preferably 10 mM sulfobetaine, where the sulfobetaine is preferably NDSB256 (3-(benzyldimethylammonio) propanesulfonate); (c) the solution is maintained at low temperature, e.g. 3-6° C. typically 4° C., and at high pH, typically approximately pH 9.0, for at least 2 weeks (typically 3 weeks, more typically 4 weeks) before proceeding with purification.

[0131] C. Protein Crystals.

[0132] Described herein is a crystal of BACE having a hexagonal space group P6₁22, and unit cell dimensions a=b=103.2 Å, c=169.1 Å, α=β=60°, γ=120°. Unit cell variability of 5% may be observed in all dimensions. Such crystals contain one copy of BACE in the asymmetric unit.

[0133] Such a crystal may be obtained using the methods described in the accompanying examples.

[0134] The crystal may be of the BACE protein of SEQ ID 19 although as explained earlier any homologue, allelic form, species variant, derivative or mutein (as hereinbefore defined) may be used. Thus, it will be understood by those of skill in the art that some variation to the primary amino acid sequence may be made without significant alteration to the resulting crystal structure. Such minor variations include the replacement of one or more amino acids, for example from 1 to 30, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids by an equivalent or fewer number of amino acids.

[0135] The methodology used to provide a BACE crystal illustrated herein may be used generally to provide a human BACE apo crystal resolvable at a resolution of at least 3 Å.

[0136] The invention thus further provides an apo BACE crystal having a resolution better than, i.e. numerically lower than, 2.5 Å.

[0137] The invention also provides a BACE crystal having a resolution better than, i.e. numerically lower than, 1.8 Å.

[0138] The invention also provides apo crystals of BACE resolvable to at least 2.5 Å capable of being soaked with compound(s) to form co-complex structures.

[0139] The proteins may be wild-type proteins or variants thereof, which are modified to promote crystal formation, for example by N-terminal truncations and/or deletion of loop regions, which prevent crystal formation.

[0140] The methods described herein may be used to make a BACE protein crystal, particularly of a BACE protein of SEQ ID 19-21, which method comprises growing a crystal by vapour diffusion using a reservoir buffer that contains 18-26% PEG 5000 MME, preferably 20-24% PEG 5000 MME, more preferably 20-22.5% PEG 5000 MME, with 180-220 mM (e.g. 200 mM) ammonium iodide and 180-220 mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6). In a preferred embodiment, this reservoir buffer may also contain from 0 to 5% glycerol, e.g. about 2.5% glycerol. The growing of the crystal is by vapour diffusion and is performed by placing an aliquot of the protein solution on a cover slip as a hanging drop above a well containing the reservoir buffer. The concentration of the protein solution used was approximately 7 mg/ml.

[0141] Other crystals of the invention include crystals which have selected coordinates of the binding pocket, wherein the amino acid residues associated with those selected coordinates are located in a protein framework which holds these amino acids in a relative spatial configuration corresponding to the spatial configuration of those amino acids in Table 1. By “corresponding to”, it is meant within an rm.s.d. of less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å from the Cα or backbone atoms of Table 1, preferably the Cα atoms.

[0142] Crystals of the invention also include crystals of BACE mutants (muteins). In addition, BACE mutants may be crystallized in co-complex with known BACE substrates or inhibitors or novel compounds.

[0143] As explained herein, a mutant BACE (or BACE mutein) is a BACE protein characterized by the replacement or deletion of at least one amino acid from the wild type BACE. Such a mutant may be prepared for example by site-specific mutagenesis, or incorporation of natural or unnatural amino acids.

[0144] As explained herein, the present invention therefore contemplates BACE mutants (or muteins) as hereinbefore defined.

[0145] For example, the BACE mutants may define a polypeptide which is obtained by replacing at least one amino acid residue in a native or synthetic BACE with a different amino acid residue and/or by adding and/or deleting amino acid residues within the native polypeptide or at the N- and/or C-terminus of a polypeptide corresponding to BACE, and which has substantially the same three-dimensional structure as BACE from which it is derived. By having substantially the same three-dimensional structure is meant having a set of atomic structure co-ordinates that have a root mean square deviation (r.m.s.d.) of less than or equal to about 2.0 Å (preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å) when superimposed with the atomic structure co-ordinates of the BACE from which the mutant is derived when at least about 50% to 100% of the C_(α) atoms of the BACE are included in the superposition. A mutant may have, but need not have, enzymatic or catalytic activity.

[0146] To produce homologues or mutants, amino acids present in the said protein can be replaced by other amino acids having similar properties, for example hydrophobicity, hydrophobic moment, antigenicity, propensity to form or break α-helical or β-sheet structures, and so. Substitutional variants of a protein are those in which at least one amino acid in the protein sequence has been removed and a different residue inserted in its place. Amino acid substitutions are typically of single residues but may be clustered depending on functional constraints e.g. at a crystal contact. Preferably amino acid substitutions will comprise conservative amino acid substitutions. Insertional amino acid variants are those in which one or more amino acids are introduced. This can be amino-terminal and/or carboxy-terminal fusion as well as intrasequence. Examples of amino-terminal and/or carboxy-terminal fusions are affinity tags, MBP tag, and epitope tags.

[0147] Deletional variants are those in which one or more amino acids are removed. This can be amino-terminal and/or carboxy-terminal, or in an internal region (for example a loop region), for example to remove or shorten that region.

[0148] Amino acid substitutions, deletions and additions that do not significantly interfere with the three-dimensional structure of the BACE will depend, in part, on the region of the BACE where the substitution, addition or deletion occurs. In highly variable regions of the molecule, non-conservative substitutions as well as conservative substitutions may be tolerated without significantly disrupting the three-dimensional structure of the molecule. In highly conserved regions, or regions containing significant secondary structure, conservative amino acid substitutions are preferred.

[0149] As explained earlier, conservative amino acid substitutions are well known in the art, and include substitutions made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the amino acid residues involved. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; amino acids with uncharged polar head groups having similar hydrophilicity values include the following: leucine, isoleucine, valine; glycine, alanine; asparagine, glutamine; serine, threonine; phenylalanine, tyrosine. Other conservative amino acid substitutions are well known in the art.

[0150] In some instances, it may be particularly advantageous or convenient to substitute, delete and/or add amino acid residues to a BACE binding pocket or catalytic residue in order to provide convenient cloning sites in the cDNA encoding the polypeptide, to aid in purification of the polypeptide, to modify compound binding etc. Such substitutions, deletions and/or additions which do not substantially alter the three dimensional structure of BACE will be apparent to those having skills in the art.

[0151] It should be noted that the mutants (BACE muteins) contemplated herein need not exhibit enzymatic activity. Indeed, amino acid substitutions, additions or deletions that interfere with the catalytic activity of the BACE but which do not significantly alter the three-dimensional structure of the catalytic region are specifically contemplated by the invention. Such crystalline polypeptides, or the atomic structure co-ordinates obtained there from, can be used to identify compounds that bind to the protein.

[0152] The crystallization of such mutants and the determination of the three-dimensional structures by X-ray crystallography relies on the ability of the mutant proteins to yield crystals that diffract at high resolution. The mutant protein could then be used to obtain information on compound binding through the determination of mutant protein/ligand complex structures, which may be characterized using the BACE crystal structure of Table 1.

[0153] The mutations can be introduced by site-directed mutagenesis e.g. using a Stratagene QuikChange™ Site-Directed Mutagenesis Kit or cassette mutagenesis methods (see e.g. Ausubel et al., eds., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., New York, and Sambrook et al., Molecular Cloning: a Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989)).

[0154] To the extent that the present invention relates to BACE-ligand complexes and mutant, homologue, allelic form, species variant, derivative, mutein and analogue proteins of BACE, crystals of such proteins may be formed. The skilled person would recognize that the conditions provided herein for crystallising BACE may be used to form such crystals. Alternatively, the skilled person would use the conditions as a basis for identifying modified conditions for forming the crystals.

[0155] Thus the aspects of the invention relating to crystals of BACE, may be extended to crystals of mutant/mutein, homologue, allelic form, species variant or derivative (as defined herein).

[0156] D. Crystal Coordinates

[0157] In a further aspect, the invention also provides an apo crystal structure of BACE having the three dimensional atomic coordinates of Table 1. An advantageous feature of the structure defined by the atomic coordinates is that it has a high resolution of about 1.75 Å. A further advantageous aspect is the provision of an apo structure of BACE, which contains no ligand bound, unlike those previously described in the art. This is particularly advantageous as ligands can then be easily soaked into the crystal to provide co-complex data without the need for removal of any ligand already present, and without the need for time-consuming co-crystallisation experiments.

[0158] The BACE structure set out in Table 1 is a monomer structure. This is the first time that a monomer has been observed crystallographically for this protein.

[0159] Table 1 gives atomic coordinate data for BACE. In Table 1 the third column denotes the atom type, the fourth the residue type, the fifth the chain identification, the sixth the residue number (the atom numbering as described in Hong et al, 2000) the seventh, eighth and ninth columns are the X, Y, Z coordinates respectively of the atom in question, the tenth column the occupancy of the atom, the eleventh the temperature factor of the atom, the twelfth the chain identification, and the last, thirteenth column, the atom type.

[0160] Each of the tables is presented in an internally consistent format. For example, in Table 1 the coordinates of the atoms of each amino acid residue are listed such that the backbone nitrogen atom is first, followed by the C-alpha backbone carbon atom, designated CA, followed by the carbon and oxygen of the protein backbone and finally side chain residues (designated according to one standard convention). Alternative file formats (e.g. such as a format consistent with that of the EBI Macromolecular Structure Database (Hinxton, UK)) which may include a different ordering of these atoms, or a different designation of the side-chain residues, may be used or preferred by others of skill in the art. However it will be apparent that the use of a different file format to present or manipulate the coordinates of the Tables is within the scope of the present invention.

[0161] The coordinates of Table 1 provide a measure of atomic location in Ångstroms, to 3 decimal places. The coordinates are a relative set of positions that define a shape in three dimensions, but the skilled person would understand that an entirely different set of coordinates having a different origin and/or axes could define a similar or identical shape. Furthermore, the skilled person would understand that varying the relative atomic positions of the atoms of the structure so that the root mean square deviation of the residue backbone atoms (i.e. the nitrogen-carbon-carbon backbone atoms of the protein amino acid residues) is less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å when superimposed on the coordinates provided in Table 1 for the Cα atoms or residue backbone atoms, will generally result in a structure which is substantially the same as the structure of Table 1 in terms of both its structural characteristics and usefulness for structure-based analysis of BACE-interactivity molecular structures.

[0162] Likewise the skilled person would understand that changing the number and/or positions of the water molecules and/or substrate molecules of Table 1 will not generally affect the usefulness of the structure for structure-based analysis of BACE-interacting structure. Thus for the purposes described herein as being aspects of the present invention, it is within the scope of the invention if: the Table 1 coordinates are transposed to a different origin and/or axes; the relative atomic positions of the atoms of the structure are varied so that the root mean square deviation of residue backbone atoms is less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å, and most preferably less than 0.5 Å when superimposed on the coordinates provided in Table 1 for the Cα or residue backbone atoms; and/or the number and/or positions of water molecules and/or substrate molecules is varied.

[0163] Reference herein to the coordinate data of Table 1 and the like thus includes the coordinate data in which one or more individual values of the Table are varied in this way unless specified explicitly to the contrary. In a preferred aspect, reference herein to the coordinates of Table 1 or parts thereof (e.g. selected coordinates) should be taken to include coordinates having a root mean square deviation of less than 0.72 Å, and preferably less than 0.5 Å, from the Cα atoms of Table 1 or corresponding parts thereof.

[0164] By “root mean square deviation” we mean the square root of the arithmetic mean of the squares of the deviations from the mean.

[0165] Protein structure similarity is routinely expressed and measured by the root mean square deviation (r.m.s.d.), which measures the difference in positioning in space between two sets of atoms. The r.m.s.d. measures distance between equivalent atoms after their optimal superposition. The r.m.s.d. can be calculated over all atoms, over residue backbone atoms (i.e. the nitrogen-carbon-carbon backbone atoms of the protein amino acid residues), main chain atoms only (i.e. the nitrogen-carbon-oxygen-carbon backbone atoms of the protein amino acid residues), side chain atoms only or more usually over C-alpha atoms only. For the purposes of this invention, the r.m.s.d. can be calculated over any of these, using any of the methods outlined below.

[0166] Methods of comparing protein structures are discussed in Methods of Enzymology, vol 115, pg 397-420. The necessary least-squares algebra to calculate r.m.s.d. has been given by Rossman and Argos (J. Biol. Chem., vol 250, pp7525(1975)) although faster methods have been described by Kabsch (Acta Crystallogr., Section A, A92, 922 (1976); Acta Cryst. A34, 827-828 (1978)), Hendrickson (Acta Crystallogr., Section A, A35, 158 (1979) and McLachan (J. Mol. Biol., vol 128, pp49 (1979). Some algorithms use an iterative procedure in which the one molecule is moved relative to the other, such as that described by Ferro and Hermans (Ferro and Hermans, Acta Crystallographic, A33, 345-347 (1977)). Other methods e.g. Kabsch's algorithm locate the best fit directly.

[0167] It is usual to consider C-alpha atoms and the rmsd can then be calculated using programs such as LSQKAB (Collaborative Computational Project 4. The CCP4 Suite: Programs for Protein Crystallography, Acta Crystallographica, D50, (1994), 760-763), MNYFIT (part of a collection of programs called COMPOSER, Sutcliffe, M. J., Haneef, I., Carney, D. and Blundell, T. L. (1987) Protein Engineering, 1, 377-384), MAPS (Lu, G. An Approach for Multiple Alignment of Protein Structures (1998, in manuscript)), QUANTA (Jones et al., Acta Crystallography A47 (1991), 110-119 and commercially available from Accelerys, San Diego, Calif.), Insight (commercially available from Accelerys, San Diego, Calif.), Sybyl® (commercially available from Tripos, Inc., St Louis), O (Jones et al., Acta Crystallographica, A47, (1991), 110-119), and other coordinate fitting programs.

[0168] In, for example the programs LSQKAB and O, the user can define the residues in the two proteins that are to be paired for the purpose of the calculation. Alternatively, the pairing of residues can be determined by generating a sequence alignment of the two proteins, programs for sequence alignment are discussed in more detail in Section G. The atomic coordinates can then be superimposed according to this alignment and an r.m.s.d. value calculated. The program Sequoia (C. M. Bruns, I. Hubatsch, M. Ridderström, B. Mannervik, and J. A. Tainer (1999) Human Glutathione Transferase A4-4 Crystal Structures and Mutagenesis Reveal the Basis of High Catalytic Efficiency with Toxic Lipid Peroxidation Products, Journal of Molecular Biology 288(3): 427-439) performs the alignment of homologous protein sequences, and the superposition of homologous protein atomic coordinates. Once aligned, the r.m.s.d. can be calculated using programs detailed above. For sequence identical, or highly identical, the structural alignment of proteins can be done manually or automatically as outlined above. Another approach would be to generate a superposition of protein atomic coordinates without considering the sequence.

[0169] It is more normal when comparing significantly different sets of coordinates to calculate the r.m.s.d. value over C-alpha atoms only. It is particularly useful when analysing side chain movement to calculate the r.m.s.d. over all atoms and this can be done using LSQKAB and other programs.

[0170] Varying the atomic positions of the atoms of the structure by up to about 0.5 Å in a concerted way, preferably up to about 0.3 Å in any direction will result in a structure which is substantially the same as the structure of Table 1 in terms of both its structural characteristics and utility e.g. for molecular structure-based analysis.

[0171] Also, modifications in the BACE crystal structure due to e.g. mutations, additions, substitutions, and/or deletions of amino acid residues (including the deletion of one or more BACE protomers) could account for variations in the BACE atomic coordinates. However, atomic coordinate data of BACE modified so that a ligand that bound to one or more binding sites of BACE would be expected to bind to the corresponding binding sites of the modified BACE are, for the purposes described herein as being aspects of the present invention, also within the scope of the invention. Reference herein to the coordinates of Table 1 thus includes the coordinates modified in this way. Preferably, the modified coordinate data define at least one BACE binding cavity.

[0172] Those of skill in the art will appreciate that in many applications of the invention, it is not necessary to utilise all the coordinates of Table 1, but merely a portion of them. The term portion is intended to define a sub-set of the coordinates, which may or may not represent contiguous amino acid residues in the BACE structure. For example, as described below, in methods of modelling candidate compounds with BACE, selected coordinates of BACE may be used, for example at least 5, preferably at least. 10, more preferably at least 50 and even more preferably at least 100 atoms of the BACE structure. Likewise, the other applications of the invention described herein, including homology modelling and structure solution, and data storage and computer assisted manipulation of the coordinates, may also utilise all or a portion of the coordinates of Table 1.

[0173] E. Homology Modelling

[0174] The invention also provides a means for homology modelling of other proteins (referred to below as target BACE proteins). By “homology modelling”, it is meant the prediction of related BACE structures based either on X-ray crystallographic data or computer-assisted de novo prediction of structure, based upon manipulation of the coordinate data of Table 1.

[0175] “Homology modelling” extends to target BACE proteins, which are analogues or homologues of the BACE protein whose structure has been determined in the accompanying examples. It also extends to BACE protein mutants of BACE protein itself.

[0176] The term “homologous regions” describes amino acid residues in two sequences that are identical or have similar (e.g. aliphatic, aromatic, polar, negatively charged, or positively charged) side-chain chemical groups. Identical and similar residues in homologous regions are sometimes described as being respectively “invariant” and “conserved” by those skilled in the art.

[0177] In general, the method involves comparing the amino acid sequences of the BACE protein of Table 1 with a target BACE protein by aligning the amino acid sequences (Dunbrack et al., Folding and Design, 2, (1997), 27-42). Amino acids in the sequences are then compared and groups of amino acids that are homologous (conveniently referred to as “corresponding regions”) are grouped together. This method detects conserved regions of the polypeptides and accounts for amino acid insertions or deletions.

[0178] Homology between amino acid sequences can be determined using commercially available algorithms. The programs BLAST, gapped BLAST, BLASTN, PSI-BLAST and BLAST 2 sequences (provided by the National Center for Biotechnology Information) are widely used in the art for this purpose, and can align homologous regions of two amino acid sequences. These may be used with default parameters to determine the degree of homology between the amino acid sequence of the Table 1 protein and other target BACE proteins, which are to be modeled.

[0179] Analogues are defined as proteins with similar three-dimensional structures and/or functions with little evidence of a common ancestor at a sequence level.

[0180] Homologues are defined as proteins with evidence of a common ancestor, i.e. likely to be the result of evolutionary divergence and are divided into remote, medium and close sub-divisions based on the degree (usually expressed as a percentage) of sequence identity.

[0181] A homologue is defined here as a protein with at least 15% sequence identity or which has at least one functional domain, which is characteristic of BACE.

[0182] There are two types of homologue: orthologues and paralogues. Orthologues are defined as homologous genes in different organisms, i.e. the genes share a common ancestor coincident with the speciation event that generated them. Paralogues are defined as homologous genes in the same organism derived from a gene/chromosome/genome duplication, i.e. the common ancestor of the genes occurred since the last speciation event.

[0183] The homologues could also be mutants as described in section (C).

[0184] Once the amino acid sequences of the polypeptides with known and unknown structures are aligned, the structures of the conserved amino acids in a computer representation of the polypeptide with known structure are transferred to the corresponding amino acids of the. polypeptide whose structure is unknown. For example, a tyrosine in the amino acid sequence of known structure may be replaced by, a phenylalanine, the corresponding homologous amino acid in the amino acid sequence of unknown structure.

[0185] The structures of amino acids located in non-conserved regions may be assigned manually by using standard peptide geometries or by molecular simulation techniques, such as molecular dynamics. The final step in the process is accomplished by refining the entire structure using molecular dynamics and/or energy minimization.

[0186] Homology modelling as such is a technique that is well known to those skilled in the art (see e.g. Greer, Science, Vol. 228, (1985), 1055, and Blundell et al, Eur. J. Biochem, Vol. 172, (1988), 513). The techniques described in these references, as well as other homology modelling techniques, generally available in the art, may be used in performing the present invention.

[0187] Thus the invention provides a method of homology modelling comprising the steps of: (a) aligning a representation of an amino acid sequence of a target BACE protein of unknown three-dimensional structure with the amino acid sequence of the BACE of Table 1 to match homologous regions of the amino acid sequences; (b) modelling the structure of the matched homologous regions of said target BACE of unknown structure on the corresponding regions of the BACE structure as defined by Table 1; and (c) determining a conformation (e.g. so that favorable interactions are formed within the target BACE of unknown structure and/or so that a low energy conformation is formed) for said target BACE of unknown structure which substantially preserves the structure of said matched homologous regions.

[0188] Preferably one or all of steps (a) to (c) are performed by computer modelling.

[0189] The aspects of the invention described herein which utilise the BACE structure in silico may be equally applied to homologue models of BACE obtained by the above aspect of the invention, and this application forms a further aspect of the present invention. Thus having determined a conformation of a BACE by the method described above, such a conformation may be used in a computer-based method of rational drug design as described herein.

[0190] The absence of a ligand from our structure is particularly advantageous for modelling of other proteins as this structure reveals the native structure of the protein unaffected by conformational changes upon ligand binding.

[0191] F. Structure Solution

[0192] The structure of the human BACE can also be used to solve the crystal structure of other target BACE proteins including other crystal forms of BACE, mutants, and co-complexes of BACE, where X-ray diffraction data or NMR spectroscopic data of these target BACE proteins has been generated and requires interpretation in order to provide a structure.

[0193] In the case of BACE, this protein may crystallize in more than one crystal form. The structure coordinates of BACE, or portions thereof, as provided by this invention are particularly useful to solve the structure of those other crystal forms of BACE. They may also be used to solve the structure of BACE mutants, BACE co-complexes, or of the crystalline form of any other protein with significant amino acid sequence homology to any functional domain of BACE.

[0194] In the case of other target BACE proteins, particularly the BACE proteins referred to in Section C above, the present invention allows the structures of such targets to be obtained more readily where raw X-ray diffraction data is generated.

[0195] Thus, where X-ray crystallographic or NMR spectroscopic data is provided for target BACE-ligand complex, or a BACE homologue or analogue of unknown three-dimensional structure, the structure of BACE, as defined by Table 1, may be used to interpret that data to provide a likely structure for the other BACE by techniques which are well known in the art, e.g. phasing in the case of X-ray crystallography and assisting peak assignments in NMR spectra.

[0196] One method that may be employed for these purposes is molecular replacement. In this method, the unknown crystal structure, whether it is another crystal form of BACE, a BACE mutant, or a BACE co-complex, or the crystal of a target BACE protein with amino acid sequence homology to any functional domain of BACE, may be determined using the BACE structure coordinates of this invention as provided herein. This method will provide an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.

[0197] Examples of computer programs known in the art for performing molecular replacement are CNX (Brunger A. T.; Adams P. D.; Rice L. M., Current Opinion in Structural Biology, Volume 8, Issue 5, October 1998, Pages 606-611 (also commercially available from Accelerys San Diego, Calif.) or AMORE (Navaza, J. (1994). AMoRe: an automated package for molecular replacement. Acta Cryst. A50, 157-163).

[0198] Thus, in a further aspect of the invention provides a method for determining the structure of a protein, which method comprises; providing the co-ordinates of Table 1, and either (a) positioning the co-ordinates in the crystal unit cell of said protein so as to provide a structure for said protein or (b) assigning NMR spectra Peaks of said protein by manipulating the coordinates of Table 1.

[0199] In a preferred aspect of this invention the co-ordinates are used to solve the structure of target BACE particularly homologues of BACE for example aspartic proteases such as BACE2 or cathepsin E (69% and 37% similarity, respectively).

[0200] G. Computer Systems

[0201] In another aspect, the present invention provides systems, particularly a computer system, the systems containing either (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE or at least selected coordinates thereof; (b) structure factor data (where a structure factor comprises the amplitude and phase of the diffracted wave) for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a target BACE protein generated by interpreting X-ray crystallographic data or

[0202] NMR data by reference to the data of Table 1; or (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0203] For example the computer system may comprise: (i) a computer-readable data storage medium comprising data storage material encoded with the computer-readable data; (ii) a working memory for storing instructions for processing said computer-readable data; and (iii) a central-processing unit coupled to said working memory and to said computer-readable data storage medium for processing said computer-readable data and thereby generating structures and/or performing rational drug design. The computer system may further comprise a display coupled to said central-processing unit for displaying said structures.

[0204] The invention also provides such systems containing atomic coordinate data of target BACE proteins wherein such data has been generated according to the methods of the invention described herein based on the starting data provided by Table 1.

[0205] Such data is useful for a number of purposes, including the generation of structures to analyze the mechanisms of action of BACE proteins and/or to perform rational drug design of compounds which interact with BACE, such as compounds which are inhibitors of BACE.

[0206] In another aspect, the invention provides a computer-readable storage medium, comprising a data storage material encoded with computer readable data, wherein the data are defined by all or a portion (e.g. selected coordinates as defined herein) of the structure coordinates of BACE of Table 1, or a homologue of BACE, wherein said homologue comprises backbone atoms that have a root mean square deviation from the Cα or backbone atoms (nitrogen-carbon_(α)-carbon) of Table 1 of less than 2 Å, such as not more than 1.5Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å.

[0207] The invention also provides a computer-readable data storage medium comprising a data storage material encoded with a first set of computer-readable data comprising a Fourier transform of at least a portion (e.g. selected coordinates as defined herein) of the structural coordinates for BACE according to Table 1; which, when combined with a second set of machine readable data comprising an X-ray diffraction pattern of a molecule or molecular complex of unknown structure, using a machine programmed with the instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data.

[0208] In a further aspect, the present invention provides computer readable media with with at least one of: (a) atomic coordinate data according to Table 1 recorded thereon, said data defining the three-dimensional structure of BACE, or at least selected coordinates thereof; (b) structure factor data for BACE recorded thereon, the structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a BACE-ligand complex or a BACE homologue or analogue generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0209] By providing such computer readable media, the atomic coordinate data can be routinely accessed to model BACE or selected coordinates thereof. For example, RASMOL (Sayle et al., TIBS, Vol. 20, (1995), 374) is a publicly available computer software package which allows access and analysis of atomic coordinate data for structure determination and/or rational drug design.

[0210] On the other hand, structure factor data, which are derivable from atomic coordinate data (see e.g. Blundell et al., in Protein Crystallography, Academic Press, New York, London and San Francisco, (1976)), are particularly useful for calculating e.g. difference Fourier electron density maps.

[0211] A further aspect of the invention provides a method of providing data for generating structures and/or performing rational drug design for BACE, BACE homologues or analogues, complexes of BACE with a potential modulator, or complexes of BACE homologues or analogues with potential modulators, the method comprising:

[0212] (i) establishing communication with a remote device containing computer-readable data comprising at least one of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE, at least one sub-domain of the three-dimensional structure of BACE, or the coordinates of a plurality of atoms of BACE; (b) structure factor data for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE homologue or analogue generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d); and (ii) receiving said computer-readable data from said remote device.

[0213] Thus the remote device may comprise e.g. a computer system or computer readable media of one of the previous aspects of the invention. The device may be in a different country or jurisdiction from where the computer-readable data is received. The communication may be via the internet, intranet, e-mail etc. Typically the communication will be electronic in nature, but some or all of the communication pathway may be optical, for example, over optical fibres. Additionally, the communication may be through radio signals or satellite transmissions.

[0214] H. Uses of the Crystals of the Invention

[0215] The crystal structures obtained according to the present invention (including the structure of Table 1 as well the structures of target BACE proteins obtained in accordance with the methods described herein), may be used in several ways for drug design.

[0216] By identifying conditions under which high quality crystals of apo-BACE can be produced (i.e. crystals which can diffract X-rays for the determination of atomic coordinates to a resolution of better than 2.5 Å), the present invention facilitates the identification of modulators of BACE activity.

[0217] The invention is particularly suitable for the design, screening, development and optimization of BACE inhibitor components. It is thus a preferred aspect of the invention that modulators are inhibitors.

[0218] In a further aspect, the invention provides a method for determining the structure of a compound bound to BACE, said method comprising: (a) providing a crystal of BACE according to the invention; (b) soaking the crystal with said compounds; and (c) determining the structure of said BACE compound complex by employing the data of Table 1.

[0219] Alternatively, the BACE and compound may be co-crystallized. Thus the invention provides a method for determining the structure of a compound bound to BACE, said method comprising; mixing the protein with the compound(s), crystallizing the protein-compound(s) complex; and determining the structure of said BACE-compound(s) complex by reference to the data of Table 1.

[0220] A mixture of compounds may be soaked or co-crystallized with the crystal, wherein only one or some of the compounds may be expected to bind to the BACE. As well as the structure of the complex, the identity of the complexing compound(s) is/are then determined.

[0221] In either case, substrate or a substrate analogue thereof may optionally be present.

[0222] The method may comprise the further steps of: (a) obtaining or synthesising said candidate modulator; (b) forming a complex of BACE and said candidate modulator; and (c) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said candidate modulator to interact with BACE.

[0223] The analysis of such structures may employ (i) X-ray crystallographic diffraction data from the complex and (ii) a three-dimensional structure of BACE, or at least selected coordinates thereof, to generate a difference Fourier electron density map of the complex, the three-dimensional structure being defined by atomic coordinate data according to Table 1. The difference Fourier electron density map may then be analyzed, to identify the binding mode of the modulator.

[0224] Therefore, such complexes can be crystallized and analyzed using X-ray diffraction methods, e.g. according to the approach described by Greer et al., J. of Medicinal Chemistry, Vol. 37, (1994), 1035-1054, and difference Fourier electron density maps can be calculated based on X-ray diffraction patterns of soaked crystals of BACE or co-crystallized BACE and the solved structure of uncomplexed BACE. These maps can then be analyzed e.g. to determine whether and where a particular compound binds to BACE and/or changes the conformation of BACE.

[0225] Electron density maps can be calculated using programs such as those from the CCP4 computing package (Collaborative Computational Project 4. The CCP4 Suite: Programs for Protein Crystallography, Acta Crystallographica, D50, (1994), 760-763.). For map visualization and model building programs such as “O” (Jones et al., Acta Crystallographica, A47, (1991), 110-119) or “QUANTA” (1994, San Diego, Calif.: Molecular Simulations can be used.

[0226] The crystal structures of a series of complexes may then be solved by molecular replacement and compared with that of the BACE of Table 1. Potential sites for modification within the various binding sites of the enzyme may thus be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between BACE and a chemical entity or compound.

[0227] All of the complexes referred to above may be studied using well-known X-ray diffraction techniques and may be refined against 1.5 to 3.5 Å resolution X-ray data to an R value of about 0.30 or less using computer software, such as CNX (Brunger et al., Current Opinion in Structural Biology, Vol. 8, Issue 5, October 1998, 606-611, and commercially available from Accelerys, San Diego, Calif.), X-PLOR (Yale University, ©1992, distributed by Accelerys), as described by Blundell et al, (1976) and Methods in Enzymology, vol. 114 & 115, H. W. Wyckoff et al., eds., Academic Press (1985).

[0228] This information may thus be used to optimize known classes of BACE substrates or inhibitors, and more importantly, to design and synthesize novel classes of BACE inhibitors.

[0229] Analysing the complex by X-ray crystallography will determine the ability of the candidate compound to interact with BACE. Analysis of the co-complexes of BACE may involve e.g. phasing, molecular replacement or calculating a Fourier difference map of the complex as discussed above. However, with the high resolutions obtainable with the crystal, it can also be possible to determine the ability of the candidate modulator to interact with BACE merely by comparing the intensities and/or positions of X-ray diffraction spots from the. complex with e.g. diffraction spots of uncomplexed BACE or a previously identified BACE-ligand complex. Thus the step of analysing the complex may involve analysing the intensities and/or positions of X-ray diffraction spots from the complex to determine the ability of the candidate modulator to interact with BACE.

[0230] Having obtained and characterized a modulator compound according to the invention, the invention further provides a method for modulating the activity of BACE which method comprises: (a) providing BACE under conditions where, in the absence of modulator, the BACE is able to synthesize amyloid β-peptide from amyloid precursor protein (APP); (b) providing a modulator compound; and (c) determining the extent to which the activity of BACE is altered by the presence of said compound.

[0231] T. Structure-based Drug Design

[0232] Determination of the three-dimensional structure of BACE provides important information about the binding sites of BACE, particularly when comparisons are made with similar enzymes. This information may then be used for rational design of BACE inhibitors, e.g. by computational techniques which identify possible binding ligands for the binding sites, by enabling linked-fragment approaches to drug design, and by enabling the identification and location of bound ligands using X-ray crystallographic analysis. These techniques are discussed in more detail below.

[0233] Greer et al. (1994) describes an iterative approach to ligand design based on repeated sequences of computer modelling, protein-ligand complex formation and X-ray crystallographic or NMR spectroscopic analysis. Thus novel thymidylate synthase inhibitor series were designed de novo by Greer et al., and BACE inhibitors may also be designed in the this way. More specifically, using e.g. GRID on the solved 3D structure of BACE, a ligand (e.g. a potential inhibitor) for BACE may be designed that complements the functionalities of the BACE binding sites. The ligand can then be synthesised, formed into a complex with BACE, and the complex then analysed by X-ray crystallography to identify the actual position of the bound ligand. The structure and/or functional groups of the ligand can then be adjusted, if necessary, in view of the results of the X-ray analysis, and the synthesis and analysis sequence repeated until an optimised ligand is obtained. Related approaches to structure-based drug design are also discussed in Bohacek et al., Medicinal Research Reviews, Vol. 16, (1996), 3-50.

[0234] Linked-fragment approaches to drug design also require accurate information on the atomic coordinates of target receptors. The basic idea behind these approaches is to determine (computationally or experimentally) the binding locations of plural ligands to a target molecule, and then construct a molecular scaffold to connect the ligands together in such a way that their relative binding positions are preserved. The ligands may be provided computationally and modelled in a computer system, or provided in an experimental setting, wherein crystals according to the invention are provided and a plurality of ligands soaked separately or in mixed pools into the crystal prior to X-ray analysis and determination of their location.

[0235] The binding site of two or more ligands are determined and may be connected to form a potential lead compound that can be further refined using e.g. the iterative technique of Greer et al. For a virtual linked-fragment approach see Verlinde et al., J. of Computer-Aided Molecular Design, 6, (1992), 131-147, and for NMR and X-ray approaches see Shuker et al., Science, 274, (1996), 1531-1534 and Stout et al., Structure, 6, (1998), 839-848. The use of these approaches to design BACE inhibitors is made possible by the determination of the BACE structure.

[0236] Many of the techniques and approaches to structure-based drug design described above rely at some stage on X-ray analysis to identify the binding position of a ligand in a ligand-protein complex. A common way of doing this is to perform X-ray crystallography on the complex, produce a difference Fourier electron density map, and associate a particular pattern of electron density with the ligand. However, in order to produce the map (as explained e.g. by Blundell et al. (1976)) it is necessary to know beforehand the protein 3D structure (or at least the protein structure factors). Therefore, determination of the BACE structure also allows difference Fourier electron density maps of BACE-ligand complexes to be produced, which can greatly assist the process of rational drug design.

[0237] The provision of the crystal structures of the invention will also allow the development of compounds which interact with the binding pocket regions of BACE (for example to act as inhibitors of a BACE) based on a fragment linking or fragment growing approach.

[0238] For example, the binding of one or more molecular fragments can be determined in the protein binding pocket by X-ray crystallography. Molecular fragments are typically compounds with a molecular weight between 100 and 200 Da (Carr et al, 2002). This can then provide a starting point for medicinal chemistry to optimize the interactions using a structure-based approach. The fragments can be combined onto a template or used as the starting point for ‘growing out’ an inhibitor into other pockets of the protein (Blundell et al, 2002). The fragments can be positioned in the binding pocket of BACE and then ‘grown’ to fill the space available, exploring the electrostatic, van der Waals or hydrogen-bonding interactions that are involved in molecular recognition. The potency of the original weakly binding fragment thus can be rapidly improved using iterative structure-based chemical synthesis.

[0239] At one or more stages in the fragment growing approach, the compound may be synthesized and tested in a biological system for its activity. This can be used to guide the further growing out of the fragment.

[0240] Where two fragment-binding regions are identified, a linked fragment approach may be based upon attempting to link the two fragments directly, or growing one or both fragments in the manner described above in order to obtain a larger, linked structure, which may have the desired properties.

[0241] The previous aspects of the invention relate also to fragment linking or fragment growing approaches to rational drug design. Thus the step of providing the structure of a candidate modulator molecule in the previous aspects may be performed by providing the structures of a plurality of molecular fragments and linking the molecular fragments to form a candidate modulator molecule. Furthermore the step of fitting the structure of the candidate modulator molecule in the previous aspects may be performed by fitting the structure of each of the molecular fragments (before or after the molecular fragments are linked together).

[0242] For example, the-computer-based method of rational drug design may comprise:

[0243] (a) providing the coordinates of at least two atoms of the BACE of Table 1; (b) providing the structures of a plurality of molecular fragments; (c) fitting the structure of each of the molecular fragments to the selected coordinates of the BACE; and (d) assembling the molecular fragments into a single molecule to form a candidate modulator molecule.

[0244] In practice, it will be desirable to model a sufficient number of atoms of the BACE as defined by the coordinates of Table 1, which represent a binding pocket. Thus, in this embodiment of the invention, there will preferably be provided the coordinates of at least 5, preferably at least 10, more preferably at least 50 and even more preferably at least 100 preferably at least 500 selected atoms of the BACE structure.

[0245] A further aspect of the invention provides a compound having a chemical structure selected using the method of any one of the previous aspects, said compound being an inhibitor of BACE.

[0246] J. Uses of the Coordinates of the Invention in In Silico Analysis and Design

[0247] Although the invention will facilitate the determination of actual crystal structures comprising BACE and a compound, which modulates BACE, current computational techniques provide a powerful alternative to the need to generate such crystals and generate and analyze diffraction data. Accordingly, a particularly preferred aspect of the invention relates to in silico methods directed to the analysis and development of compounds, which interact, with BACE structures of the present invention.

[0248] The approaches to structure-based drug design described below all require initial identification of possible compounds for interaction with target bio-molecule (in this case BACE). Sometimes these compounds are known e.g. from the research literature. However, when they are not, or when novel compounds are wanted, a first stage of the drug design program may involve computer-based in silico screening of compound databases (such as the Cambridge Structural Database) with the aim of identifying compounds which interact with the binding site or sites of the target bio-molecule. Screening selection criteria may be based on pharmacokinetic properties such as metabolic stability and toxicity. However, determination of the BACE structure allows the architecture and chemical nature of each BACE binding site to be identified, which in turn allows the geometric and functional constraints of a descriptor for the potential inhibitor to be derived. The descriptor is, therefore, a type of virtual 3-D pharmacophore, which can also be used as selection criteria or filter for database screening.

[0249] Thus as a result of the determination of the BACE three-dimensional structure, more purely computational techniques for rational drug design may also be used to design BACE inhibitors (for an overview of these techniques see e.g. Walters et al (Drug Discovery Today, Vol.3, No.4, (1998), 160-178; Abagyan, R.; Totrov, M. Curr. Opin. Chem. Biol. 2001, 5, 375-382). For example, automated ligand-receptor docking programs (discussed e.g. by Jones et al. in Current Opinion in Biotechnology, Vol.6, (1995), 652-656 and Halperin, I.; Ma, B.; Wolfson, H.; Nussinov, R. Proteins 2002, 47, 409-443), which require accurate information on the atomic coordinates of target receptors may be used to design potential BACE inhibitors.

[0250] The aspects of the invention described herein which utilize the BACE structure in silico may be equally applied to both the BACE structure of Table 1 and the models of target BACE proteins obtained by other aspects of the invention. Thus having determined a conformation of a BACE by the method described above, such a conformation may be used in a computer-based method of rational drug design as described herein. In addition the availability of the structure of the BACE will allow the generation of highly predictive pharmacophore models for virtual library screening or compound design.

[0251] Accordingly, the invention provides a computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing the structure of a BACE of the invention of Table 1; (b) providing a molecular structure to be fitted to said BACE structure; and (c) fitting the molecular structure to the BACE structure of Table 1.

[0252] In an alternative aspect, the method of the invention may utilize the coordinates of atoms of interest of BACE, which are in the vicinity of a putative molecular structure binding region, for example within 10-25 Å of the catalytic regions or within 5-10 Å of a compound bound, in order to model the pocket in which the structure binds. These coordinates may be used to define a space, which is then analyzed “in silico”. Thus the invention provides a computer-based method for the analysis of molecular structures which comprises: (a) providing the coordinates of at least two atoms of a BACE structure of the invention (“selected coordinates”); (b) providing the structure of a molecular structure to be fitted to said coordinates; and (c) fitting the structure to the selected coordinates of the BACE.

[0253] In practice, it will be desirable to model a sufficient number of atoms of the BACE as defined by the coordinates of Table 1, which represent a binding pocket. Thus, in this embodiment of the invention, there will preferably be provided the coordinates of at least 5, preferably at least 10, more preferably at least 50 and even more preferably at least 100 and preferably 500 selected atoms of the BACE structure.

[0254] In order to provide a three-dimensional structure of compounds to be fitted to a BACE structure of the invention, the compound structure may be modelled in three dimensions using commercially available software for this purpose or, if its crystal structure is available, the coordinates of the structure may be used to provide a representation of the compound for fitting to a BACE structure of the invention.

[0255] The step of providing the structure of a candidate modulator molecule may involve selecting the compound by computationally screening a database of compounds for interaction with the binding cavity or cavities. For example, a 3-D descriptor for the potential modulator may be derived, the descriptor including geometric and functional constraints derived from the architecture and chemical nature of the binding cavity or cavities. The descriptor may then be used to interrogate the compound database, a potential modulator being a compound that has a good match to the features of the descriptor. In effect, the descriptor is a type of virtual pharmacophore.

[0256] In any event, the determination of the three-dimensional structure of BACE provides a basis for the design of new and specific ligands for BACE. For example, knowing the three-dimensional structure of BACE, computer modelling programs may be used to design different molecules expected to interact with possible or confirmed binding cavities or other structural or functional features of BACE. Examples of this are discussed in Schneider, G.; Bohm, H. J. Drug Discov.Today 2002, 7, 64-70.

[0257] More specifically, the interaction of a compound with BACE can be examined through the use of computer modelling using a docking program such as GOLD (Jones et al., J. Mol. Biol., 245, 43-53 (1995), Jones et al., J. Mol. Biol., 267, 727-748 (1997)), GRAMM (Vakser, I. A., Proteins, Suppl., 1:226-230 (1997)), DOCK (Kuntz et al, J.Mol.Biol. 1982, 161, 269-288, Makino et al, J.Comput.Chem. 1997, 18, 1812-1825), AUTODOCK (Goodsell et al, Proteins 1990, 8, 195-202, Morris et al, J.Comput.Chem. 1998, 19, 1639-1662.), FlexX, (Rarey et al, J.Mol.Biol. 1996, 261, 470-489) or ICM (Abagyan et al, J.Comput.Chem. 1994, 15, 488-506). This procedure can include computer fitting of compounds to BACE to ascertain how well the shape and the chemical structure of the compound will bind to the BACE.

[0258] Also computer-assisted, manual examination of the binding site structure of BACE may be performed. The use of programs such as GRID (Goodford, J. Med. Chem., 28, (1985), 849-857)—a program that determines probable interaction sites between molecules with various functional groups and an enzyme surface—may also be used to analyse the binding cavity or cavities to predict partial structures of inhibiting compounds.

[0259] Computer programs can be employed to estimate the attraction, repulsion, and steric hindrance of the two binding partners (i.e. the BACE and a candidiate modulator). Generally the tighter the fit, the fewer the steric hindrances, and the greater the attractive forces, the more potent the potential modulator since these properties are consistent with a tighter binding constant. Furthermore, the more specificity in the design of a potential drug, the more likely it is that the drug will not interact with other proteins as well. This will tend to minimise potential side-effects due to unwanted interactions with other proteins.

[0260] In another aspect, the present invention provides a method for identifying an agent compound (e.g. an inhibitor) which modulates BACE activity, comprising the steps of: (a) employing three-dimensional atomic coordinate data according to Table 1 to characterise at least one BACE binding site and preferably a plurality of BACE binding sites; (b) providing the structure of a candidate agent compound; (c) fitting the candidate agent compound to the binding sites; and (d) selecting the candidate agent compound.

[0261] Preferably sufficient binding sites are characterised to define a BACE binding cavity or cavities.

[0262] A plurality (for example two, three or four) of (typically spaced) BACE binding sites may be characterised and a plurality of respective compounds designed or selected. The agent compound may then be formed by linking the respective compounds into a larger compound which preferably maintains the relative positions and orientations of the respective compounds at the binding sites. The larger compound may be formed as a real molecule or by computer modelling.

[0263] In one embodiment a plurality of candidate agent compounds are screened or interrogated for interaction with the binding sites. In one example, step (b) involves providing the structures of the candidate agent compounds, each of which is then fitted in step (c) to computationally screen a database of compounds (such as the Cambridge Structural Database) for interaction with the binding sites, i.e. the candidate agent compound may be selected by computationally screening a database of compounds for interaction with the binding sites (see Martin, J. Med Chem., vol 35, 2145-2154 (1992)). In another example, a 3-D descriptor for the agent compound is derived, the descriptor including e.g. geometric and functional constraints derived from the architecture and chemical nature of the binding cavity or cavities. The descriptor may then be used to interrogate the compound database, the identified agent compound being the compound which matches with the features of the descriptor. In effect, the descriptor is a type of virtual pharmacophore.

[0264] In a related aspect, the present invention provides a method for identifying a candidate modulator (e.g. potential inhibitor) of BACE comprising the steps of: (a) employing a three-dimensional structure of BACE, at least one sub-domain thereof, or a plurality of atoms thereof, to characterise at least one BACE binding cavity, the three-dimensional structure being defined by atomic coordinate data according to Table 1; and (b) identifying the candidate modulator by designing or selecting a compound for interaction with the binding cavity.

[0265] Detailed structural information can then be obtained about the binding of the compound to BACE, and in the light of this information adjustments can be made to the structure or functionality of the compound, e.g. to improve its interaction with BACE. The above steps may be repeated and re-repeated as necessary.

[0266] K. Compound Selection

[0267] In another aspect, in place of in silico methods, high throughput screening of compounds to select compounds with binding activity may be undertaken, and those compounds which show binding activity may be selected as possible candidate modulators, and further crystallized with BACE (e.g. by co-crystallization or by soaking) for X-ray analysis. The resulting X-ray structure may be compared with that of Table 1 for a variety of purposes.

[0268] L. Compounds of the Invention

[0269] Having designed or selected possible binding candidate modulators (e.g. by in silico analysis, “wet” chemical methods, X-ray analysis etc.) by determining those which have favourable fitting properties (e.g. strong attraction between candidate and BACE), these can then be screened for activity.

[0270] Consequently all the methods of compound design and identification outlined above can optionally include the step of: (a) obtaining or synthesising the candidate modulator; and (b) contacting the candidate modulator with BACE to determine the ability of the candidate modulator to interact with BACE.

[0271] More preferably, in the latter step the candidate modulator is contacted with BACE under conditions to determine its function.

[0272] For example, in the contacting step above the candidate modulator is contacted with BACE in the presence of a substrate, and typically a buffer, to deter mine the ability of said candidate modulator to inhibit BACE. The substrate may be e.g. APP. So, for example, an assay mixture for BACE may be produced which comprises the candidate modulator, substrate and buffer.

[0273] Detailed structural information can be obtained about the binding of the candidate modulator to BACE, and in the light of this information adjustments can be made to the structure or functionality of the candidate modulator, e.g. to improve binding to the binding cavity or cavities. The above steps may be repeated and re-repeated as necessary.

[0274] Following identification of such compounds, it may be manufactured and/or used in the preparation, i.e. manufacture or formulation, of a composition such as a medicament, pharmaceutical composition or drug. These may be administered to individuals.

[0275] Thus, the present invention extends in various aspects not only to a compound as provided by the invention, but also a pharmaceutical composition, medicament, drug or other composition comprising such a compound e.g. for treatment (which may include preventative treatment) of disease; a method comprising administration of such a composition to a patient, e.g. for treatment of disease; use of such an inhibitor in the manufacture of a composition for administration, e.g. for treatment of disease; and a method of making a pharmaceutical composition comprising admixing such an inhibitor with a pharmaceutically acceptable excipient, vehicle or carrier, and optionally other ingredients.

[0276] Thus a further aspect of the present invention provides a method for preparing a medicament, pharmaceutical composition or drug, the method comprising:

[0277] (a) identifying a BACE modulator molecule (which may thus be termed a lead compound) by a method of any one of the other aspects of the invention disclosed herein; (h) optimising the structure of the modulator molecule; and (c) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.

[0278] The above-described processes of the invention may be iterated in that the modified compound may itself be the basis for further compound design.

[0279] By “optimising the structure” we mean e.g. adding molecular scaffolding, adding or varying functional groups, or connecting the molecule with other molecules (e.g. using a fragment linking approach) such that the chemical structure of the modulator molecule is changed while its original modulating functionality is maintained or enhanced. Such optimisation is regularly undertaken during drug development programmes to e.g. enhance potency, promote pharmacological acceptability, increase chemical stability etc. of lead compounds.

[0280] Modification will be those conventional in the art known to the skilled medicinal chemist, and will include, for example, substitutions or removal of groups containing residues which interact with the amino acid side chain groups of a BACE structure of the invention. For example, the replacements may include the addition or removal of groups in order to decrease or increase the charge of a group in a test compound, the replacement of a charge group with a group of the opposite charge, or the replacement of a hydrophobic group with a hydrophilic group or vice versa. It will be understood that these are only examples of the type of substitutions considered by medicinal chemists in the development of new pharmaceutical compounds and other modifications may be made, depending upon the nature of the starting compound and its activity.

[0281] Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0282] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like may be used. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc, an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. 15th Edition, 1975.

[0283] Compositions may be used, e.g. for treatment (which may include preventative treatment) of a disease such as Alzheimer's disease or Alzheimer's-type pathology in Downs syndrome. Thus the invention provides a method comprising administration of such a composition to a patient, e.g. for treatment of a disease such as Alzheimer's disease; use of such an agent compound in the manufacture of a composition for administration, e.g. for treatment of a disease such as Alzheimer's disease; and a method of making a pharmaceutical composition comprising admixing such an agent compound with a pharmaceutically acceptable excipient, vehicle or carrier, and optionally other ingredients.

EXEMPLIFICATION

[0284] The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the invention described. These examples constitute the best mode currently contemplated for practicing the invention;

[0285] BACE protease was expressed at high levels in bacterial cells as insoluble inclusion bodies. To prepare functional protein for enzyme assay and structural studies these inclusion bodies were solublised using denaturants; the slow removal of these denaturants allowed the formation of the correct tertiary structure. In the method described here, BACE was expressed as a pro-sequence and required activation by a protease before becoming fully functional. Clostripain was used as an activating protease but produced multiple species of BACE as determined by mass spectrometry. In order to obtain a uniform homogenous protein after activation by clostripain, a number of different constructs were produced. These constructs focused on the mutation of two undesireable clostripain cleavage sites (following residues R56 and R57).

[0286] Cloning of BACE WT and BACE N->Q

[0287] The full-length DNA coding sequence of BACE was cloned from human cerebellum and human dorsal root ganglion (DRG) cDNA by PCR using oligonucleotide primers based on the published BACE sequence (EMBL accession no. AF190725). The full-length template sequence was obtained by PCR amplification using the following primers: hBACE-sp1 and -ap1 I were used for primary amplification, hBACE-sp2 and -ap2 for nested PCR.

[0288] The primers were as follows: hBACE-sp1 5′-AGCTCCCTCTCCTGAGAAGCCACC-3′ (SEQ ID NO: 22) hBACE-ap1 5′-CCACAGGTGCCATCTGTGTCTCC-3′ (SEQ ID NO: 23) hBACE-sp2 5′-CACCAGCACCACCCAGACTTGG-3′ (SEQ ID NO: 24) hBACE-ap2 5′-AACCACGGAGGTGTGGTCCAGG-3′ (SEQ ID NO: 25)

[0289] A cDNA construct encoding a modified BACE form was made as follows. A partial BACE cDNA fragment was amplified using the full-length BACE clone as a template with primers hBACE_EC(Bam-M-14)_FOR (5′-CGG GAT CCA TGG CGG GAG TGC TGC TGC CTG CC-3′) and hBACE_EC(Bam-453)_REV (5′-CGG GAT CCT TAT GAC TCA TCT GTC TGT GGA ATG TTG TAG C-3′). The resulting 1342 bp PCR fragment was subcloned in vector pCR2.1-TOPO using the TOPO TA cloning® kit (Invitrogen) according to the manufacturer's instructions. The inserts of several resulting clones were fully sequenced and a clone containing no PCR mistakes was selected. The insert of this clone was excised from the pCR2.1-TOPO construct using the BamHI restriction endonuclease and subcloned to vector pET11a (Novagen) linearized with BamHI. The BACE coding sequence (BACE WT, SEQ ID 1) in the resulting clones was confirmed by sequence analysis and the resulting correct construct was named M-T7-RGSM(BACE14-453)/pET11a.

[0290] Plasmid M-T7-RGSM(BACE14-453)/pET11a encodes a 455 amino acid residue protein named BACE WT containing a T7 epitope tag encoded by the pET11a vector sequence (AA 1 to 11), a linker sequence (AA 12-15; RGSM) and the partial BACE amino acid sequence from residue 14 to 453 (AA 16 to 455)(numbering based on SEQ ID 2). The calculated molecular mass of the resulting protein is 50.2 kDa.

[0291] The insert from construct Plasmid M-T7-RGSM(BACE14-453)/pET11 a was amplified by PCR to incorporate a His₆ tag (CAT CAC CAT CAT CAC CAC) just upstream of the stop codon and BamH1 site. Following cloning of this amplified fragment back into the original expression vector, the asparagine residues at positions -153, -172, -223 and -354 (numbers refer to the database BACE sequence BACE_HUMAN, P56817 in Swissprot) were mutated to glutamine (AAC to CAA) using the Quikchange™ mutagenesis system (Stratagene, used according to the manufacturers instructions), to generate BACE N->Q (SEQ ID 3).

[0292] Introduction of Activation Site Mutations

[0293] BACE WT and BACE N->Q, described above, were mutated using the Quickchange™ site directed mutagenesis protocol (Stratagene). Two complimentary oligonucleotides were designed which spanned the site of the mutation and which incorporated the amino acids changes to be made. These oligonucleotides were then used as primers in a PCR reaction producing each of the strands of the plasmid with the mutation present; the parental plasmid is digested with the methylation sensitive restriction endonuclease DpnI and then transformed into competent E. coli cells.

[0294] Primers were applicable for the mutation of both BACE WT and BACE N->Q due to their high sequence homology. Seven constructs were produced; these are detailed below with the oligonucleotide sequence used to make the constructs.

[0295] 1) BACE WT mutating arginine 56 to lysine and arginine 57 to lysine (SEQ ID 5) (SEQ ID NO: 26) 5′-CCCGAGGAGCCCGGCAAGAAGGGCAGCTTTGTGGAGATG-3′ (SEQ ID NO: 27) 5′-CATCTCCACAAAGCTGCCCTTCTTGCCGGGCTCCTCGGG-3′

[0296] 2) BACE WT mutating arginine 57 to lysine (SEQ ID 7) (SEQ ID NO: 28) 5′-CCCGAGGAGCCCGGCCGGAAGGGCAGCTTTGTGGAGATGG-3′ (SEQ ID NO: 29) 5′-CCATCTCCACAAAGCTGCCCTTCCGGCCGGGCTCCTCGGG-3′

[0297] 3) BACE WT deleting arginine 57 (SEQ ID 9) (SEQ ID NO: 30) 5′-CCCGAGGAGCCCGGCAGGGGCAGCTTTGTGGAGATGGTGGAC-3′ (SEQ ID NO: 31) 5′-GTCCACCATCTCCACAAAGCTGCCCCTGCCGGGCTCCTCGGG-3′

[0298] 4) BACE N->Q mutating arginine 56 to lysine and arginine 57 to lysine (SEQ ID 11) (SEQ ID NO: 32) 5′-CCCGAGGAGCCCGGCAAGAAGGGCAGCTTTGTGGAGATG-3′ (SEQ ID NO: 33) 5′-CATCTCCACAAAGCTGCCCTTCTTGCCGGGCTCCTCGGG-3′

[0299] 5) BACE N->Q mutating arginine 57 to lysine (SEQ ID 15) (SEQ ID NO: 34) 5′-CCCGAGGAGCCCGGCCGGAAGGGCAGCTTTGTGGAGATGG-3′ (SEQ ID NO:35) 5′-CCATCTCCACAAAGCTGCCCTTCCGGCCGGGCTCCTCGGG-3′

[0300] 6) BACE N->Q deleting arginine 57 (SEQ ID 17) (SEQ ID NO: 36) 5′-CCCGAGGAGCCCGGCAGGGGCAGCTTTGTGGAGATGGTGGAC-3′ (SEQ ID NO: 37) 5′-GTCCACCATCTCCACAAAGCTGCCCCTGCCGGGCTCCTCGGG-3′

[0301] 7) BACE N->Q mutating arginine 56 to lysine and arginine 57 to lysine and removing the C terminal poly histidine tag (SEQ ID 13) (SEQ ID NO: 38) 5′-CCCGAGGAGCCCGGCAAGAAGGGCAGCTTTGTGGAGATG-3′ (SEQ ID NO: 39) 5′-CATCTCCACAAAGCTGCCCTTCTTGCCGGGCTCCTCGGG-3′ (SEQ ID NO: 40) 5′-CCACAGACAGATGAGTCATGACACCATCATCACCACTAAG-3′ (SEQ ID NO: 41) 5′-CTTAGTGGTGATGATGGTGTCATGACTCATCTGTCTGTGG-3′

[0302] After transformation of the plasmid the protein coding region was checked by DNA sequencing.

[0303] Protein Production (1)

[0304] Plasmid constructs were transformed into BLR(DE3) as follows: 1-2 μl DNA was added into 25 ul BLR(DE3) competent cells. Cells were then heat shocked at 42° C. for 45 secs, followed by incubation for 30 mins at 4° C. The sample was placed on ice for 2-3 mins before addition of 125-250 ul HOC medium and left for 60 mins at 37° C. Cells were plated out onto agar containing carbenicillin & incubated at 37° C. for 16 h. Transformations were stored at 4° C. Transformed cells could be used up to after 8 weeks storage.

[0305] Colonies were inoculated in 100 ml LB broth with 1 mM carbenicillin, and shaken for 16 h at 25° C. 12 ml of this culture was added to 1 L of the same medium in baffle flasks. The typical total culture volume was 12, 20 or 24 L. Cells were induced by addition of 1 mM IPTG at approximately OD₆₀₀ 1.0. Cells were harvested 3 to 4 hours after induction by centrifugation for 7 min at 16000 g. Cell pellets were resuspended in 1 liter TN buffer (150 mM NaCl, 50 mM Tris, pH 7.5) before addition of 10 mg lysozyme per liter of bacterial culture. The suspension was left for 20 mins under vigorous stirring then frozen at −70° C.

[0306] The lysates were thawed & adjusted to 1 mM MgCl12 and 20 μl 10 mg/ml DNAse, incubated 30-60 mins at 20° C., then 0.1% Triton X-100 was added. Inclusion body washes were performed in 11 wash steps, spun down at 13,000-16,000 g for 20 mins at room temperature then resuspended by sonication in TNT buffer (TN buffer +0.1% Triton 100). The washing step with TNT was repeated at least three times (up to seven times) until an almost homogenous dark cream precipitate was obtained. At this stage the pellet was washed twice with TN buffer. The typical yield for a 12 L culture of BACE WT constructs was 4.5 g washed inclusion body material.

[0307] Protein Refolding (1)

[0308] Each g of inclusion bodies was solubilised with 22.5 ml of 8 M urea, 50 mM Tris, 0.1 M beta-mercaptoethanol, 10 mM DTT, 1 mM EDTA. After 2 to 3 hours under gentle stirring, this was spun at 48400 g for 25 mins. This was then diluted 1 in 10 in 8 M Urea, 0.2 mM oxidized glutathione, 1.0 mM reduced glutathione. This is the starting solution for refolding

[0309] Refolding was accomplished by dilution into 20 volumes 20 mM Tris, 10 mM NDSB256 (3-(benzyldimethylammonio)propanesulfonate). The addition was achieved by slowly dripping from a burette into a strongly stirred solution. Addition was carried out at room temperature.

[0310] The pH was adjusted to approximately 9 using 13.5 ml 1 N HCl per 5 liter of refolding mix either immediately after dilution or 16 h after dilution. This was left at 4° C. for 2-3 weeks. The refolding mix was then adjusted to pH 8.2 16h before concentrating. In instances where a longer incubation was applied it appeared that yields were slightly better. No precipitation was seen when attempting to refold BACE, even in totally unsuccessful conditions. Constructs BACE WT R57K, BACE WT R57DEL, BACE N->Q R57K, and BACE R57DEL refolded with lower yields.

[0311] Protein Purification of BACE from Refolding Step (1)

[0312] The refolded protein sample was concentrated by ultrafiltration using two parallel Vivaflow 200 cells (MWCO 30 Kda), fed by a single pump. The concentration factor was not more than 200 times: if exceeded, precipitation occurred.

[0313] Concentrated refolded BACE was loaded and eluted on a 1.75 L Sephacryl 300 column run at a flow of 0.2 cm-1/min in 0.4 M Urea, 20 mM Tris, 10 mM HCl. Typical loading volume was 2% bed volume. From reconcentrated material three peaks are observed, the first one near the void volume (large aggregates), which merges into a second peak of aggregated inactive material. The third peak (elutes at approx 40% of column volume) constitutes active BACE. For BACE WT constructs, the active fraction elutes at approximately 800 ml.

[0314] Activation by Clostripain (1)

[0315] Clostripain (Cp; EC 3.4.22.8, from Worthington or Sigma C7403) was activated before use by solubilising the freeze dried material to 1.25 mg/ml in: 20 mM Calcium Acetate, 8 mM DTT, 100 mM Tris, pH 8 at 1.25 mg/ml 4 ° C for at least I h. The preparation was then stable at 4 ° C for up to four weeks.

[0316] The third peak (typically 100 ml at an average of 0.3 mg ml) from Sephacryl 300 elution was treated with activated Cp, (1/100 dilution) for between 30-90mins at room temperature.

[0317] Activation of BACE WT R56KR57K, BACE N->Q R56KR57K & BACE N->Q R56KR57K no His by clostripain was performed as described above except that prior to activation the solution was concentrated ten fold using Vivaspin 20 ml 30 KDa MWCO.

[0318] The reaction was stopped by loading onto a Mono Q HR5-5 column equilibrated in 0.4 M Urea, 20 mM Tris, 10 mM HCI, 1 mM EDTA followed by washing using the same buffer. The protein was eluted with a 0 to 1 M NaCl gradient over 10 column volumes. A typical final yield of active soluble BACE WT R56KR5!K is 1-2 mg of protein per liter of culture grown. The eluted protein was characterised and used in crystallisation assays.

Protein Production (2)

[0319] BLR (DE3) competent cells were transformed as described earlier and plated onto agar containing ampicillin (Amp). A colony was picked into 250ml LB +100 ug/ml Amp and grown overnight ( 37° C, 1 85rpm. Following overnight growth (OD₆₀₀ varied between 2.0- 2.5) 10 ml of this culture was used to inoculate IL of fresh LB+100 ₁₁g/ml Amp in a 2L baffled flask. Routinely 24L of fresh LB+Amp would be inoculated from the overnight growth. Following inoculation, the 24L prep would be grown at 37° C., 185rpm until an OD₆₀₀ =1.0 was obtained. Protein expression was induced by the addition of IPTG to a final concentration of 1 mM. Cultures were incubated for a further 3 hours (at 37° C., 185rpm) before harvesting by centrifugation at 8000 rpm for 10 mins (JLA 8.1000). Cell pellets could be stored at -800C or processed immediately.

[0320] All following protein production procedures were performed at room temperature unless stated otherwise. Cell pellet was re-suspended in 500ml of TN buffer (TN buffer - 1 5OmM NaCl, 50 mM Tris, pH7.5). 240mg of egg lysozyme (10 mg/L of bacterial culture) was added to the re-suspended pellet. The suspension was left stirring for 20mins. Following this, 100 ul of DNase 1 (10 mg/ml stock) was added to the suspension and this was left stirring for 20mins. This lysate was clarified by centrifugation at 8000rpm for 20mins (JLA8. l000).

[0321] The supernatant was discarded and the pellet was re-suspended in 100 ml TNT buffer (TNT buffer—150 mM NaCl, 5 mM Tris, pH7.5, 0.1% Triton X-100). Effort was made to break up any lumps present in the pellet so that a homogenous re-suspension was obtained. Following this, the re-suspension was sonicated for 2 mins (20 sec pulses). 400 ml of TNT buffer was added to bring the volume of the suspension up to ˜500 mls. This was centrifuged for 20 mins at 8000 rpm and the supernatant discarded. The re-suspension in TNT buffer and sonication steps, as described above, were repeated twice. Following these three TNT washes, the pellet was re-suspended in 100 ml of TN buffer and sonicated for 2 mins (20 second pulses). The suspension was centrifuged for 20 mins at 8000 rpm. This wash in TN buffer was repeated once. Approximately 12-15 g of inclusion bodies was obtained from the 24L of culture.

[0322] Protein Refolding (2)

[0323] The inclusion body preparation was solubilised by addition of 100 mls of solubilisation buffer (Sol. Buffer—8M urea, 50 mM Tris, 0.1M beta-mercaptoethanol, 10 mM DTT, 1 mM EDTA). Effort was made to break up the inclusion body pellet using a pipette/spatula. The solution was left stirring gently overnight. The suspension was centrifuged for 30 mins at 25,000 rpm (JA25). The supernatant (˜100 mls) was diluted by the addition of 900 mls of 8M urea, 0.2 mM oxidised glutathione, 1.0M reduced glutathione.

[0324] The 1L of solubilised inclusion bodies as prepared above were refolded by a further 20× dilution. A 250 ml aliquot of solubilised inclusion body prep was added drop-wise to 4.75L of refolding buffer (Refolding buffer—20 mM Tris, 10 mM NDSB256 (3-(benzyldimethylammonio)propanesulfonate). The 4.75L of refolding buffer was stirred vigorously (not foaming) and the 250 mls of inclusion body prep was added using a peristaltic pump. Care was taken to add the 250 mls at a fast drop rather than a continuous pour. The remaining 750 mls of inclusion body prep was diluted in the same way (250 mls into 4.75L of refolding buffer). The four 5L vessels were placed at 4° C. overnight.

[0325] Following overnight incubation at 4° C., the pH of each 5L vessel was adjusted to pH9.0 by addition of conc HCl. The vessels were then placed back at 4° C. and left for 3 weeks.

[0326] Protein Purification of BACE from Refolding Step (2)

[0327] Two parallel Vivaflow 200 cells (MWCO 30 Kda) fed by a single peristaltic pump were used. Each 5L of refolding mix was concentrated to ˜50 mls. Over concentrating leads to precipitation and should be avoided. The concentration of 5L of refolding mix took ˜2 hours. The 50 mls of concentrated refolding mix was centrifuged for 25 mins, at 25,000 rpm. The supernatant was then ready for gel filtration using a Sephacryl S-300 column (100×3.5). This method is limited by the volume of concentrated refolding mix than can be loaded onto the gel filtration column (50 mls) per run. Sephacryl S-300 column was equilibrated with 0.4M urea, 20 mM Tris, 10 mM HCl (at a flow rate of 4 ml/min). 50 ml of sample can be loaded per run. The column was run at a flow rate of 4 ml/min. SDS PAGE analysis of peaks 1,2 and 3 showed the presence of BACE (50 Kda band) however activity assay of all three peaks showed only active BACE in peak 3. Fractions from Peak 3 were pooled and kept on ice.

[0328] Activation by Clostripain (2)

[0329] Clostripain (Sigma C7403) was prepared by dissolving protein to a final concentration of 1.25 mg/ml in 20 mM Calcium acetate, 8 mM DTT, 100 mM Tris pH 8.0. The clostripain was activated by incubating on ice for 1 hour prior to use.

[0330] Pooled fractions from peak 3 (˜100 ml at 0.2 mg/ml) were activated by the addition of 1/100 dilution of 1.25 mg/ml clostripain. The reaction was incubated at 37° C. in a water bath for 90 minutes. The reaction was stopped by addition of 1 mM EDTA and placed on ice. Note: With each fresh batch of Sigma Clostripain, a time trial was performed on a small amount of BACE to verify the length of incubation needed at 37° C. The length of incubation varied from 30-90 mins. Analysis by SDS PAGE clearly showed the appearance of the lower molecular weight activated species (˜47 Kda) from the larger inactivated species (˜50 Kda).

[0331] A Mono Q 5/5 ion exchange column was pre-equilibrated in 0.4M urea, 20 mM Tris, 10 mM HCl. The activated BACE (˜50 mls at ˜0.2 mg/ml) was loaded onto the Mono Q column at a flow rate of 1.0 ml/min. Activated BACE was purified by applying a linear salt gradient (0.4M urea, 20 mM Tris, 10 mM HCl, 1.0M NaCl) over 20 column volumes. Following analysis by SDS PAGE and subsequent activity assay, fractions corresponding to activated BACE were pooled and buffer exchanged into crystallisation buffer (20 mM Tris, pH8.2, 150 mM NaCl, 1 mM DTT).

[0332] Protein Purification of BACE from Refolding Step (3)

[0333] By using method 3 in conjunction with the S-200 INDEX gel filtration column, all 20L of refolding mix could be processed in one go.

[0334] A Sartocon filtration cassette (MWCO 30 Kda) was used in conjunction with a Watson Marlow 623S high speed pump. This assembly was set up as described in the manufactures operation manual. The 20L of refolding mix was concentrated down to ˜500 mls in less than 1 hour. Due to the dead volume in the assembly tubing, the volume could not be reduced further. At this stage the 500 mls of concentrated refolding mix was filtered using a 0.2 um filter. The filtered sample was then ready for gel filtration using an S-200 INDEX gel filtration column (100×10.0). A S-200 INDEX column pre-equilibrated in 0.4M urea, 20 mm Tris, 10 mM HCl was used. The column run was at a flow rate of 10 mls/min.

[0335] SDS analysis of peaks 1,2 and 3 showed that BACE was present in all fractions. Activity assay showed that only peak 3 contain some BACE activity. Fractions from peak 3 were pooled (˜250 mls at 0.1 mg/ml).

[0336] Prior to clostripain activation, the BACE sample was concentrated using a Resource Q ion exchange column. A 6/1 Resource Q column was pre-equilibrated in 0.4M urea, 20 mM Tris, 10 mM HCl. The Bace sample was loaded onto the column at 7 ml/min. BACE was eluted off the column using a linear salt gradient (0.4M urea, 20 mM Tris, 10 mM HCl, 1M NaCl) over 5 column volumes. This step has the effect of dramatically reducing the sample volume size. Prior to clostripain activation, the protein sample is diluted with 0.4M urea, 20 mM Tris, 10 mM HCl to reduce the salt concentration to enable further purification using Mono Q. A dilution factor of 5:1 has been used successfully.

[0337] This is then followed by Clostripain Activation and Mono Q purification as outlined above.

[0338] Protein Characterization

[0339] The quality of the final preparation was evaluated by:

[0340] (a) SDS polyacrylamide gel electrophoresis, performed using commercial gels (Novagen) followed by Coomassie Brilliant Blue staining according to the manufacturer's instructions. The purity as estimated by scanning a digital image of a gel was estimated to be at least 95%.

[0341] (b) Mass Spectroscopy: The eluted peak(s) were analysed using ESI-TOF-MS. Mass spectroscopy was performed using a Bruker “BioTOF” electrospray time of flight instrument. Samples were either diluted by a factor of 1000 straight from storage buffer into methanol/water/formic acid (50:48:2 v/v/v), or subjected to reverse phase HPLC separation using a C4 column. Calibration was achieved using Bombesin and angiotensin I using the 2+ and 1+ charged states. Data were acquired between 200 and 2000 m/z range and were subsequently processed using Bruker's X-mass program. Mass accuracy was typically below 1 in 10000.

[0342] MS Analysis of BACE WT R56KR57K (SEQ ID NO: 6)

[0343] Full-length protein: MASMTGGQQMGRGSMAGVLPAHGT . . .

[0344] Predicted mass of full-length protein: 50147

[0345] Cleavage position:

[0346] MASMTGGQQMGR⇓GSMAGVLPAHGT . . .

[0347] Predicted mass of BACE protein: 48911. This is the first intermediate fragment and is obtained very quickly and can be obtained as a stable fragment at lower enzyme concentration.

[0348] Cleavage position: MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLR↓ LPRETDEEP . . .

[0349] Predicted mass of BACE protein: 45781. This is the final fragment obtained in the conditions described above. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 45783. The fragment typically elutes as a single peak from the Mono Q 5.5.

[0350] Mass Spec Analysis of BACE N->Q R56KR57K (SEQ ID NO: 12)

[0351] Predicted mass of full-length protein: 50895

[0352] Cleavage position: MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLR↓ LPRETDEEP . . .

[0353] Predicted mass of BACE protein: 46660.65. This is the final fragment obtained in the conditions described above. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 46655. The fragment typically elutes as two peaks from the Mono Q 5.5, the first corresponding to the desired fragment.

[0354] Mass Spec Analysis of BACE N->Q R56KR57K no His (SEQ ID NO: 14)

[0355] Predicted mass of full-length protein: 50072.73

[0356] Cleavage position: MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLR ↓ LPRETDEEP . . .

[0357] Predicted mass of BACE protein: 45837.80. This is the first intermediate fragment, obtained rapidly between 30-60 minutes post activation and is suitable for crystallisation. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 45838.30. Typically elutes as 2 peaks from the Mono Q 5.5, the first peak corresponding to the desired fragment. MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETD EEPEEPGK ↓ KGSFVEMV . . .

[0358] Cleavage position:

[0359] Predicted fragment mass: 44230.11. Further digestion beyond 60 minutes promotes the formation of the above fragment, not suitable for crystallisation. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 44228.03. This typically elutes as peak 2 from the Mono Q 5.5.

[0360] Method for Determining Activity of BACE

[0361] A fluorimetric assay was used to measure the activity of the refolded proteins. Activity of the BACE enzyme was measured using the fluorescent peptide R-E(EDANS)-E-V-N-L-*D-A-E-F-K(DABCYL)-R-OH (Bachem) as substrate. Assays were carried out in 96-well black, flat-bottomed Cliniplates in a final assay volume of 100 ul. The reaction rate was monitored at room temperature on a Fluoroskan Ascent plate reader with excitation and emission wavelengths of 355 nm and 530 nm respectively.

[0362] To determine the pH profile for the enzyme 8 nM BACE was incubated with 10 μM substrate in 50 mM sodium acetate (pH 3.5-5.5) or MES (pH 5.5-6.5) buffers at varying pHs and 5% DMSO.

[0363] For kinetic characterization of the enzyme 8 nM BACE enzyme was incubated with varying concentrations of the substrate (2.5-80 μM) in 50 mM sodium acetate, pH 5, 5% DMSO and the reaction monitored as described above. Kinetic parameters were determined by the standard Michaelis-Menten equation, using Prizm (GraphPad) software. 1 mM OM 99 completely inhibits activity.

[0364] Protein Crystallisation

[0365] The sample of BACE was buffer exchanged into 20 mM Tris.HCl pH8.2, 150 mM NaCl, 1 mM DTT and concentrated down to approximately 7 mg/ml as determined by its theoretical extinction coefficient. Prior to crystallisation, the sample was spun at 55,000 rpm for 30 min using a Beckman benchtop ultracentrifuge. DMSO was added to a final concentration of 3% (v/v).

[0366] Crystals of BACE from BACE WT R56KR57K, BACE N->Q R56KR57K & BACE N->Q R56KR57K no His were obtained by the hanging-vapour diffusion method at 20° C. using 1.5 μl of protein and an equivalent volume of reservoir solution. The reservoir solution contained 20-24% PEG 5000 MME, 180-220 mM (e.g. 200 mM) ammonium iodide, 180-220 mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6). In an alternative, the reservoir solution may additionally contain 2.5% v/v glycerol.

[0367] Diffraction quality single crystals of BACE WT R56KR57K were obtained by the hanging-vapour diffusion method at 20° C. using 1.5 μl of protein and an equivalent volume of reservoir solution. The reservoir solution contained 20-22.5% PEG 5000 MME, 180-220 mM (e.g. 200 mM) ammonium iodide, 180-220 mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6).

[0368] Crystals appear within the first week and grow to maximum dimensions within 14 days. The crystals were hexagonal rods with approximate dimensions of 0.2×0.05×0.05 mm. They belonged to the hexagonal space group P6₁22 with cell parameters a=b=103.2 Å, c=169.1 Å and accommodate one enzyme molecule per asymmetric unit, and a solvent content of 66%.

[0369] Inhibitor Soaking

[0370] BACE inhibitors were dissolved in DMSO to a concentration of 500 mM and then diluted 1 in 10 in a harvesting solution composed of 220 mM ammonium iodide, 220 mM sodium cacodylate pH 6.4 and 22% PEG 5K MME or 100-200 mM sodium citrate pH 5.0, 200 mM ammonium iodide and 30% PEG 5K MME. Apo-BACE protein crystals were transferred into the harvesting solution for a period of up to 24 hours prior to being dipped in cryoprotectant (20% PEG 5000 MME, 200 mM ammonium iodide, 200 mM sodium cacodylate pH 6.4 and 20% _((v/v)) glycerol or 200 mM sodium citrate pH 5.0, 200 mM ammonium iodide, 30% PEG 5K MME and 20% _((v/v)) glycerol) containing the inhibitor and frozen in liquid nitrogen.

[0371] Data Collection & Processing

[0372] The structure of apo-BACE was solved from BACE WT R56KR57K to 1.75 Å resolution using the method of molecular replacement. Prior to data collection, crystals were exposed, briefly, to cryoprotectant, described previously, before flash freezing. Data was collected at 100°K. on beamline ID14-1 at the European Synchrotron Radiation Facility using an ADSC Quantum4 CCD detector, with a wavelength of 0.934 Å and processed using MOSFLM (Leslie, A. G. W. (1992). In Joint CCP4 and EESF-EACMB Newsletter on Protein Crystallography, vol. 26, Warrington, Daresbury Laboratory). The dataset was scaled using SCALA (CCP4—Collaborative Computational Project 4. (1994) The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallographica D50, 760-763) and the intensities converted to structure factor amplitudes with TRUNCATE (Evans, P. R. (1997). Scaling of MAD data. In Recent Advances in Phasing (ed. K. S. Wilson, G. Davies, A. W. Ashton and S. Bailey), pp. 97-102. Council for the Central Laboratory of the Research Councils Daresbury Laboratory, Daresbury, UK), from the CCP4 suite of programs (CCP4—Collaborative Computational Project 4. (1994) The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallographica D50, 760-763). Statistics for the processing are shown in Table 2. TABLE 2 Data collection statistics for apo-BACE. Resolution  1.75 Å Mosaicity  0.34° Completeness 95.9% Multiplicity  6.3 Rmerge  0.097

[0373] Structure Determination and Refinement

[0374] The structure of apo-BACE was solved by molecular replacement using the program EPMR (Kissinger C R, Gehlhaar D K, Fogel D B, Acta Crystallogr D Biol Crystallogr, 1999,vol 55 (Pt 2), 484-91). Initially, it was impossible to know whether the correct space group was P6₁22 or P6₅22, therefore molecular replacement attempts were performed against both. Default parameters and a resolution range of 15-4Å were used in conjunction with the A chain of 1FKN (Hong et al, 2000) as the search model. A solution was found for P6₁22 with an Rfactor of 0.458 and a correlation coefficient of 0.543. In an attempt to reduce model bias, the molecular replacement solution was used as the starting point for ARP/wARP (Morris R J, Perrakis A, Lamzin V S, Acta Crystallogr D Biol Crystallogr, 2002,vol 58,(Pt 6 No 2), 968-75) to perform automated backbone tracing using warpNtrace and side chain building via the Side_dock procedure. This produced a discontinuous model composed of 244 out of 385 residues spanning 12 amino acid chains. Cycles of structural refinement with REFMAC5 (Murshudov, G. N., Vagin, A. A. and Dodson, E. J. (1997). Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallographica, 1997 D53, 240-255) were alternated with manual rebuilding of the model using QUANTA (Jones et al., Acta Crystallography A47 (1991), 110-119 and commercially available from Accelerys, San Diego, Calif.). The model was extended to 329 residues with chain breaks between 156-170, 255-280 and 311-325. CNX (Brunger et al., Current Opinion in Structural Biology, Vol. 8, Issue 5, October 1998, 606-611, and commercially available from Accelerys, San Diego, Calif.) composite omit maps were generated to allow further building of the structure and finally water molecules added using DenInt (Astex internal software library). Refinement statistics are shown in Table 3. TABLE 3 Final refinement statistics for apo-BACE Rwork 0.251 Rfree 0.284 RMS bond deviation from ideality 0.011 RMS bond angle deviation from ideality 1.30 Average Bfactor for structure 32.99

[0375] This data indicates that the final structure is of good quality; the Rfactors indicating that the refined model has a good agreement with the experimental data. The RMS deviations from ideality indicate that the geometry of the model is good.

[0376] Description of the Apo Structure of BACE

[0377] The structure of BACE we present here has been solved in the absence of substrate or inhibitor. This is the first time that such a structure has been described. The solution of this structure has been possible as we have, for the first time, crystallized BACE without compound in a form suitable for diffracting X-rays, and hence allowed the determination of the apo structure of BACE. Under our conditions it crystallizes in space group P6₁22 with a monomer in the asymmetric unit. This is a novel crystal form of BACE.

[0378] The protein chain has been traced in the electron density from residue Phe47p to Ala157, and then from Ala168 to Asn385. There is no indication as to the position of residues 158 to 167 in the electron density map. In addition to the protein atoms, the model contains 3 iodine atoms and 285 water molecules in its present state of refinement.

[0379] The majority of the residues in this form of BACE are well defined, the exceptions being some exposed residues. Parts of the protein surface are exposed to solvent, as a consequence of the molecular packing within the crystal lattice (FIG. 1). Residues 255-259, 271-277 and 310 to 317 are exposed and have high B-factors relative to the body of the protein. In addition, residues 304 to 309 pack against an exposed loop and are poorly ordered with high b-factors. There are three disulphide bonds in BACE, two of these are well defined in the electron density, the third, between Cys269 and Cys319 has high temperature factors. This is probably a consequence of its proximity to exposed parts of the protein.

[0380] BACE as it has been solved in this form, is a compact globular protein, which is formed by two domains; domain 1 being comprised of residues 47p-146 and domain 2 of residues (146-385)(numbering from Hong et al, 2000). The active site lies between these two domains, and contains the two conserved aspartic acid residues, Asp32 and Asp228, which define the active sites of aspartic proteinases. In our structure, a single water molecule is coordinated between these two residues.

[0381] The overall fold of the protein is similar to that of 1FKN (Hong et al, 2000), with a few minor, but potentially significant changes. Residues 158-166 are ordered in the structure of BACE in the presence of OM99-2 (in the P2₁ form), and consist of a loop plus a short helix. In the P6₁22 unliganded form, these residues cannot be seen, and are assumed to be mobile. This may be a consequence of the crystal packing arrangement in this form. Residues 69-75 have a different arrangement in the crystal form described here, to their arrangement in the crystal structure of the OM99-2 complex. The residues are displaced upward relative to the active site in the structure without OM99-2. The two molecules can be superposed over all residues using the program MAPS (MAPS-Multiple Alignment of Proteins Structures Version 0.2, Sep.-7-1999, Guoguang, Lund University, Sweden and Lu, G. An Approach for Multiple Alignment of Protein Structures (1998, in manuscript) to give an r.m.s.d. of 0.74 Å. This results in close alignment of the N-terminal residue prior to residue 69 and subsequent to 75. In contrast the CA atoms of residue 71 are displaced by 3.3 Å, those of residue 72 by 4.3 Å, and those of residue 73 by 6.0 Å. (FIG. 2) The reason for this difference is postulated to be the interaction of OM99-2 backbone residues with the protein residues, in an arrangement analogous to a beta sheet. This interaction pulls the loop down over the substrate in the active site, and locks it in position. In the absence of substrate, or peptidic inhibitor, the loop moves back up again.

[0382] In addition to these local changes in structure, on binding of inhibitor, there appears to be a slight shift in the domain positions relative to each other, resulting in an average difference in position in the C-terminal domain CA atoms of about 2.0 Å, when the molecules are superposed using the N-terminal CA atoms.

[0383] The symmetry of the P6₁22 crystal system has resulted in a packing arrangement which brings part of a symmetry related molecule very close to the active site entrance of BACE. Gln73 from a symmetry related molecule lies very close to the entrance to the active site of BACE in this crystal form, and overlaps with the position occupied by P4 Glu in OM99-2. However, this does not interfere with the usefulness of this crystal system to soak in inhibitors, as we have shown that these crystals can be used to soak BACE inhibitors into the active site.

INCORPORATION BY REFERENCE

[0384] The entire contents of all patents, published patent applications and other references cited herein are hereby expressly incorporated herein in their entireties by reference. Particular reference is made to the references listed below:

[0385] Bennett B D, Denis P, Haniu M, Teplow D B, Kahn S, Louis J C, Citron M, Vassar R. J Biol. Chem. 2000; 275(48):37712-7.

[0386] Blundell T L, Jhoti H, Abell C, Nature Reviews Drug Discovery, 1, 45-54, 2002.

[0387] Blundell, T L and Johnson, L N, in Protein Crystallography, Academic Press, New York, London and San Francisco, (1976)

[0388] Burton S J, Quirk A V, Wood P C, European Journal of Biochemistry, 179, 379-87, 1989.

[0389] Carr, R; Jhoti, H; Drug Discov. Today, 2002, 7(9), 522-527

[0390] Choppa R, Svenson K, Annis B, Akopian T, Bard J, Stahl M, Somers W; PCT International Publication Number WO 02/25276, (28 Mar. 2002).

[0391] Collaborative Computing Project N., 1994 Acta Crystallogr. D. 50 760-763.

[0392] Creemers J W, Ines Dominguez D, Plets E, Serneels L, Taylor N A, Multhaup G, Craessaerts K, Annaert W, De Strooper B., J Biol. Chem. (2001) 276(6), 4211-7

[0393] De Strooper, B. and Konig. G., 1999, Nature 402, 471-472.

[0394] Ghosh A K., Shin D., Downs D., Koelsch G., Lin X., Ernolieff J. and Tang J. (2000) J. Am. Chem. Soc. 122 3522-3523.

[0395] Goldberg M E, Expert-Bezancon N, Vuillard L, Rabilloud T, Folding & Design, 1, 21-27, 1996.

[0396] Greer J, Erickson J W, Baldwin J J, Varney M D, J. of Medicinal Chemistry, Vol. 37, (1994), 1035-1054,

[0397] Haniu M, Denis P, Young Y, Mendiaz E A, Fuller J, Hui J O, Bennett B D, Kahn S, Ross S. Burgess T, Katta V, Rogers G, Vassar R, Citron M., J Biol. Chem. (2000), 275(28), 21099-106.

[0398] Hong L., Koelsch G., Lin X., Wu S., Terzyan S., Ghosh A K., Zhang X C. and Tang J. (2000) SCIENCE 290 150-153.

[0399] Hussain I, Powell D, Howlett D R, Tew D G, Meek T D, Chapman C, Gloger I S, Murphy K E, Southan C D, Ryan D M, Smith T S, Simmons D L, Walsh F S, Dingwall C, Christie G., Mol. Cell Neurosci. (1999)14(6):419-27

[0400] Lin X., Koelsch G., Wu S., Downs D., Dashti A. and Tang J. (2000) PNAS 97 1456-1460.

[0401] Mallender W D, Yager D, Onstead L, Nichols M R, Eckman C, Sambamurti K, Kopcho L M, Marcinkeviciene J, Copeland R A, Rosenberry T L., Mol Pharmacol, (2001) Mar;59(3), 619-26

[0402] Navaza J., 1994 Acta Crystallogr. A. 50 157

[0403] Pflugrath, J W. (1999) Acta Crystallogr. D. 55 1718-1725 Sinha S., Anderson J P., Barbour R., Basi G S., Caccavello R., Davis D., Doan M., Dovey H F., Frigon N., Hong J., Jacobson-Croak K., Jewett N., Keim P., Knops J., Lieberburg I., Power M., Tan H., Tatsuno G., Tung J., Schenk D., Seubert P., Suomensaari S M., Wand S., Walker D., Zhoa J., McConlogue L. and Varghese J. (1999) NATURE 402 537-540

[0404] Tang J, Lin X, Koelsch G; PCT International Publication Number WO 01/00663, (04 Jan. 2001).

[0405] Vassar R., Bennett, B D., Babu-Khan S., Kahn S., Mendiaz, E A., Denis P., Teplow D B., Ross S., Amarante P., Loeloff R., Luo Y., Fisher S., Fuller J., Edenson S., Lile J., Jorosinski M A., Biere A L., Curran E., Burgess T., Louis J-C., Collins F., Treaner J., Rogers G. and Citron M. (1999) SCIENCE 286 735-741

[0406] Yan R., Bienkowski M J., Shuck M E., Miao H., Tory M C., Pauley A M., Brashier J R., Stratman N C., Mathews W R., Buhl A E., Carter D B., Tomasselli A G., Parodi L A., Heinrikson R L. and Gurney, M E. (1999) Nature, 402 533-537

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EQUIVALENTS

[0408] The foregoing description details presently preferred embodiments of the present invention which are therefore to be considered in all respects as illustrative and not restrictive. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents, modifications and variations to the specific embodiments of the invention described specifically herein. Such equivalents, modifications and variations are intended to be (or are) encompassed in the scope of the following paragraphs:

[0409] 1. A mutant BACE protein, which protein lacks one or more proteolytic cleavage sites recognized by clostripain (or another protease which recognizes the same cleavage site as clostripain).

[0410] 2. The protein of paragraph 1 wherein BACE residues R56 and/or R57 (based on numbering of SwissProt P56817) are mutated or deleted.

[0411] 3. The protein of paragraph 2 wherein R56 or R57 are mutated by the substitution of arginine for lysine.

[0412] 4. The protein of paragraph 2 wherein R56 and R57 are mutated by the substitution of arginine for lysine.

[0413] 5. The protein of any one of the preceding paragraphs which comprises BACE residues 56 to 396 (based on numbering of SwissProt P56817).

[0414] 6. A mutant BACE protein (for example, a mutant BACE protein as defined in any one of the preceding paragraphs) which is truncated at the N-terminal up to and including R42, R45, G55, R56 or R57.

[0415]7. The protein of any one of paragraphs 1 to 6 truncated at the C-terminal such that at least residues 454 et seq. are absent.

[0416] 8. The protein of paragraph 7 truncated at the C-terminal such that at least residues 447 et seq. are absent.

[0417] 9. The protein of any one of the preceding paragraphs wherein the asparagine residues at positions 153, 172, 223 and 354 are mutated to glutamine residues.

[0418] 10. The protein of any one of the preceding paragraphs which is un- or deglycolsylated.

[0419] 11. A mutant BACE protein selected from: (a) SEQ ID 6; (b) SEQ ID 8; (c) SEQ ID 10; (d) SEQ ID 12; (e) SEQ ID 14; (f) SEQ ID 16; (g) SEQ ID 18; (h) SEQ ID 19; (i) SEQ ID 20; Q) SEQ ID21.

[0420] 12. Nucleic acid encoding the protein of any one of the preceding paragraphs.

[0421] 13. A vector comprising the nucleic acid of paragraph 12.

[0422] 14. A host cell comprising the vector of paragraph 13.

[0423] 15. A process for producing the protein of any one of paragraphs 1 to 11 comprising the steps of: (a) culturing the host cell of paragraph 14 under conditions suitable for expression of the protein; and optionally (b) isolating the expressed recombinant BACE protein.

[0424] 16. A process for producing refolded recombinant BACE comprising the steps of: (a) solubilising the recombinant BACE; (b) diluting the solubilised BACE into an aqueous buffer containing sulfobetaine (for example at a concentration of 10 to 50 mM); and (c) maintaining the diluted solution at low temperature (for example, 3 to 6° C.) and at high pH (e.g. 9 to 10.5) for at least 2 weeks.

[0425] 17. The process of paragraph 16 wherein the recombinant BACE is produced according to the process of paragraph 15.

[0426]18. Refolded recombinant BACE produced by, or obtainable by, the process of paragraph 16 or paragraph 17.

[0427]19. A process for producing a crystal of BACE comprising the step of refolding recombinant BACE protein according to the process of paragraph 16 or paragraph 17.

[0428]20. A process for producing a crystal of BACE comprising the step of growing the crystal by vapour diffusion using a reservoir buffer that contains 18-26% PEG 5000 MME (for example, 20-24% PEG 5000 MME, e.g. 20-22.5% PEG 5000 MME), 180-220 mM (e.g. 200 mM) ammonium iodide and 180-22-mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6).

[0429] 21. The process of paragraph 20 wherein the BACE is recombinant and the process further comprises the preliminary step of refolding the recombinant BACE according to the process of paragraph 16 or paragraph 17.

[0430] 22. The process of any one of paragraphs 18 to 20 further comprising the step of activating the BACE by clostripain digestion.

[0431] 23. The process of paragraph 21 wherein the BACE is as defined in any one of paragraphs 1 to 10.

[0432] 24. A crystal of BACE produced by, or obtainable by, the process of any one of paragraphs 18 to 22.

[0433] 25. A crystal of BACE having a hexagonal space group P6₁22.

[0434] 26. The crystal of paragraph 25 having unit cell dimensions of a=b=103.2 Å, c=169.1 Å, α=β60°, γ=120°, and a unit cell variability of 5% in all dimensions.

[0435] 27. The crystal of paragraph 25 or paragraph 26 which contains one copy of BACE in the asymmetric unit.

[0436] 28. A crystal of BACE (e.g. a crystal according to any one of paragraphs 24 to 27) having a resolution better than 3 Å.

[0437] 29. The crystal of paragraph 28 having a resolution better than 2.5Å.

[0438] 30. The crystal of paragraph 29 having a resolution better than 1.8Å.

[0439] 31. A crystal of BACE (e.g. a crystal according to any one of paragraphs 24 to 30) comprising a structure defined by all or a portion of the co-ordinates of Table 1.

[0440] 32. The crystal of paragraph 31 comprising a structure defined by a portion of the coordinates of Table 1 which coordinates relate to: (a) the BACE catalytic domain; and/or (b) a BACE active site; and/or (c) a BACE binding cavity; and/or (d) selected, amino acid residues of a BACE binding cavity located in a protein framework which holds the selected amino acids in a relative spatial configuration which corresponds to the spatial configuration of those amino acids in Table 1; and/or (d) a BACE binding site.

[0441] 33. The crystal of paragraph 32 wherein the portion of the coordinates of Table 1 comprise (or consist essentially of) those relating to residues SER71, GLY72, LEU91, ASP93, GLY95, SER96, VAL130, PRO131, TYR132, THR133, GLN134, ILE171, ILE179, ILE187, ALA188, ARG189, PRO190, TRP258, TYR259, ASP284, LYS285, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and ARG368 (based on the numbering of SwissProt P56817).

[0442] 34. The crystal of paragraph 33 wherein the portion of the coordinates of Table 1 comprise (or consist essentially of) those relating to residues LYS70, SER71, GLY72, GLN73, GLY74, TYR75, LEU91, VAL92, ASP93, THR94, GLY95, SER96, SER97, ASN98, TYR129, VAL130, PRO131, TYR132, THR133, GLN134, GLY135, LYS136, TRP137, LYS168, PHE169, PHE170, ILE171, ASN172, SER174, TRP176, GLY178, ILE179, LEU180, GLY181, ALA183, TYR184, ALA185, GLU186, ILE187, ALA188, ARG189, PRO190, ASP191, ASP192, ARG256, TRP258, TYR259, TYR283, ASP284, LYS285, SER286, ILE287, VAL288, ASP289, SER290, GLY291, THR292, THR293, ASN294, LEU295, ARG296, GLY325, GLU326, ARG368, VAL370, LYS382, PHE383, ALA384, ILE385, SER386, GLN387, SER388, SER389, THR390, GLY391, THR392, VAL393, GLY395, ALA396 and ILE447 (based on the numbering of SwissProt P56817).

[0443] 35. The crystal of any one of paragraphs 24 to 34 which is capable of being soaked with compound(s) to form co-complex structures.

[0444] 36. The crystal of any one of paragraphs 24 to 35 which is soaked with one or more compound(s) to form co-complex structures.

[0445] 37. The crystal of any one of paragraphs 24 to 36 wherein the BACE is co-crystallized with one or more compound(s) to form co-crystallized structures.

[0446] 38. The crystal of any one of paragraphs 24 to 35 which is an apo crystal.

[0447] 39. The crystal of any one of paragraphs 24 to 38 wherein the BACE is a wild-type BACE.

[0448] 40. The crystal of paragraph 39 wherein the BACE is a human BACE.

[0449] 41. The crystal of paragraph 40 wherein the BACE is a homologue of a human BACE.

[0450] 42. The crystal of paragraph 41 wherein the homologue is an orthologue or a paralogue of a human BACE.

[0451] 43. The crystal of any one of paragraphs 24 to 38 wherein the BACE is a mutant and/or recombinant BACE.

[0452] 44. The crystal of paragraph 43 wherein the BACE: (a) lacks the BACE transmembrane and/or cytoplasmic domain(s); and/or (b) lacks one or more glycolsylation sites; and/or (c) comprises one or more peptide tags (for example a his tag); and/or (d) lacks one or more protease cleavage site(s); and/or (e) is truncated at the N-terminus; and/or (f) is truncated at the C-terminus; and/or (f) lacks the BACE pro-sequence.

[0453] 45. The crystal of paragraph 44 wherein the BACE mutant lacks one or more clostripain cleavage sites.

[0454] 46. The crystal of paragraph 45 wherein BACE residues R56 and/or R57 (based on numbering of SwissProt P56817) are mutated or deleted.

[0455] 47. The crystal of paragraph 46 wherein R56 or R57 are mutated by the substitution of arginine for lysine.

[0456] 48. The crystal of paragraph 46 wherein R56 and R57 are mutated by the substitution of arginine for lysine.

[0457] 49. The crystal of any one of paragraphs 43 to 48 wherein the BACE mutant is truncated at the N-terminal up to and including R42.

[0458] 50. The crystal of any one of paragraphs 43 to 49 wherein the BACE mutant is truncated at the C-terminal such that at least residues 396 et seq. are absent.

[0459] 51. The crystal of paragraph 50 wherein the BACE mutant is truncated at the C-terminal such that at least residues 387 et seq. are absent.

[0460] 52. The crystal of any one of paragraphs 43 to 51 wherein the asparagine residues at positions 153, 172, 223 and 354 of the BACE mutant are mutated to glutamine residues.

[0461] 53. The crystal of any one of paragraphs 24 to 52 wherein the BACE is un- or deglycolsylated.

[0462] 54. The crystal of paragraph 43 wherein the BACE mutant is selected from: (a) SEQ ID 19; (b) SEQ ID 20; (c) SEQ ID 21.

[0463] 55. The process of any one of paragraphs 19 to 23 wherein the process produces a crystal of BACE as defined in any one of paragraphs 24 to 54.

[0464] 56. A three-dimensional representation of BACE or of a portion of BACE, which representation comprises all or a portion of the coordinates of Table 1.

[0465] 57. The three-dimensional representation of paragraph 56 which is a model constructed from all or a portion of the coordinates of Table 1.

[0466] 58. The model of paragraph 57 wherein the portion of BACE is a BACE binding cavity and the portion of the coordinates of Table 1 comprise those of atoms defining a binding site within the binding cavity (for example, wherein the coordinates are as defined in paragraph 33 or paragraph 34).

[0467] 59. A three-dimensional representation of a compound which fits the model of paragraph 57 or paragraph 58.

[0468] 60. The three-dimensional representation of paragraph 59 which is a model of the compound.

[0469] 61. The model of paragraph 60 wherein the compound is a pharmacophore.

[0470] 62. The model of any one of paragraphs 57, 58, 60 or 61 which is: (a) a wire-frame model; (b) a chicken-wire model; (c) a ball-and-stick model; (d). a space-filling model; (e) a stick-model; (f) a ribbon model; (g) a snake model; (h) an arrow and cylinder model; (i) an electron density map; (j) a molecular surface model.

[0471] 63. The model of any one of paragraphs 57, 58, 60, 61 or 62 which is in physical form.

[0472] 64. The model of any one of paragraphs 57, 58, 60, 61 or 62 which is in electronic form.

[0473] 65. The model of paragraph 64 which comprises a graphical image display on a computer screen.

[0474] 66. A computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing a BACE model as defined in paragraph 57, 58 or 62 to 65; (b) providing a molecular structure to be fitted to said BACE model; and (c) fitting the molecular structure to the BACE model to produce a compound model as defined in paragraph 60, 61 or 62 to 65.

[0475] 67. A computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing the structure of a BACE as defined by the coordinates of Table 1; (b) providing a molecular structure to be fitted to said BACE structure; and (c) fitting the molecular structure to the BACE structure of Table 1.

[0476] 68. A computer-based method for the analysis of molecular structures which comprises: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structure of a molecular structure to be fitted to the selected coordinates; and (c) fitting the structure to the selected coordinates of the BACE structure.

[0477] 69. The method of paragraph 68 wherein the selected coordinates represent a binding pocket.

[0478] 70. The method of paragraph 68 or paragraph 69 wherein the selected coordinates are of at least 5, 10, 50 or 100 atoms.

[0479] 71. The method of paragraph 69 or paragraph 70 wherein the selected coordinates are as defined in paragraph 33 or paragraph 34.

[0480] 72. A computer-based method of rational drug design comprising the method of any one of paragraphs 66 to 71.

[0481] 73. A computer-based method of rational drug design comprising comprising: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structures of a plurality of molecular fragments; (c) fitting the structure of each of the molecular fragments to the selected coordinates; and (d) assembling the molecular fragments into a single molecule to form a candidate modulator molecule.

[0482] 74. A method for identifying a candidate modulator (e.g. candidate inhibitor) of BACE comprising the steps of: (a) employing a three-dimensional structure of BACE, at least one sub-domain thereof, or a plurality of atoms thereof, to characterise at least one BACE binding cavity, the three-dimensional structure being defined by atomic coordinate data according to Table 1; and (b) identifying the candidate modulator by designing or selecting a compound for interaction with the binding cavity.

[0483] 75. The method of paragraph 74 wherein the three-dimensional structure of BACE is a model as defined in paragraph 57 or paragraph 58.

[0484] 76. A method for identifying an agent compound (e.g. an inhibitor) which modulates BACE activity, comprising the steps of: (a) employing three-dimensional atomic coordinate data according to Table 1 to characterise at least one (e.g. a plurality of) BACE binding site(s); (b) providing the structure of a candidate agent compound; (c) fitting the candidate agent compound to the binding sites; and (d) selecting the candidate agent compound.

[0485] 77. The method of paragraph 76 wherein in step (a) the three-dimensional atomic coordinate data are employed to create a model as defined in paragraph 57, 58 or 62 to 65.

[0486] 78. The method of any one of paragraphs 73 to 77further comprising the step of: (a) obtaining or synthesising the candidate agent or modulator; and (b) contacting the candidate modulator with BACE to determine the ability of the candidate modulator to interact with BACE.

[0487] 79. A method of assessing the ability of a candidate modulator to interact with BACE which comprises the steps of: (a) obtaining or synthesising said candidate modulator; (b) forming a crystallized complex of BACE and said candidate modulator; and (c) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said candidate modulator to interact with BACE.

[0488] 80. A method for determining the structure of a compound bound to BACE, said method comprising: (a) mixing BACE with the compound to form a BACE-compound complex; (b) crystallizing the BACE-compound complex; and (c) determining the structure of said BACE-compound(s) complex by reference to the data of Table 1.

[0489] 81. A method for determining the structure of a compound bound to BACE, said method comprising: (a) providing a crystal of BACE; (b) soaking the crystal with one or more compound(s) to form a complex; and (c) determining the structure of the complex by employing the data of Table 1.

[0490] 82. A method of determining the three dimensional structure of a BACE homologue or analogue of unknown structure, the method comprising the steps of: (a) aligning a representation of an amino acid sequence of the BACE homologue or analogue with the amino acid sequence of the BACE of Table 1 to match homologous regions of the amino acid sequences; (b) modelling the structure of the matched homologous regions of said target BACE of unknown structure on the corresponding regions of the BACE structure as defined by Table 1; and (c) determining a conformation for the BACE homologue or analogue which substantially preserves the structure of said matched homologous regions.

[0491] 83. The method of paragraph 82 wherein steps (a) and/or (b) and/or (c) are performed by computer modelling.

[0492] 84. A method of providing data for generating structures and/or performing rational drug design for BACE, BACE homologues or analogues, complexes of BACE with a potential modulator, or complexes of BACE homologues or analogues with potential modulators, the method comprising: (i) establishing communication with a remote device containing computer-readable data comprising at least one of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE, at least one sub-domain of the three-dimensional structure of BACE, or the coordinates of a plurality of atoms of BACE; (b) structure factor data for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE homologue or analogue generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d); and (ii) receiving said computer-readable data from said remote device.

[0493] 85. A computer system containing one or more of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE or at least selected coordinates thereof, (b) structure factor data (where a structure factor comprises the amplitude and phase of the diffracted wave) for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a target BACE protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; or (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0494] 86. The computer system of paragraph 85 comprising: (i) a computer-readable data storage medium comprising data storage material encoded with the computer-readable data; (ii) a working memory for storing instructions for processing said computer-readable data; and (iii) a central-processing unit coupled to said working memory and to said computer-readable data storage medium for processing said computer-readable data and thereby generating structures and/or performing rational drug design.

[0495] 87. The computer system of paragraph 86 further comprising a display coupled to said central-processing unit for displaying said structures.

[0496] 88. A computer-readable storage medium, comprising a data storage material encoded with computer readable data, wherein the data are defined by all or a portion of the structure coordinates of BACE of Table 1, or a homologue of BACE, wherein said homologue comprises backbone atoms that have a root mean square deviation from the backbone atoms (nitrogen-carbon_(α)carbon) of Table 1 of not more than 1.5 Å.

[0497] 89. A computer-readable data storage medium comprising a data storage material encoded with a first set of computer-readable data comprising a Fourier transform of at least a portion (e.g. selected coordinates as defined herein) of the structural coordinates for BACE according to Table 1; which, when combined with a second set of machine readable data comprising an X-ray diffraction pattern of a molecule or molecular complex of unknown structure, using a machine programmed with the instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data.

[0498] 90. A computer readable medium with at least one of: (a) atomic coordinate data according to Table 1 recorded thereon, said data defining the three-dimensional structure of BACE, or at least selected coordinates thereof; (b) structure factor data for BACE recorded thereon, the structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a BACE-ligand complex or a BACE homologue or analogue generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0499] 91. A method for determining the structure of a protein, which method comprises;

[0500] providing the co-ordinates of Table 1, and either (a) positioning the co-ordinates in the crystal unit cell of said protein so as to provide a structure for said protein or (b) assigning NMR spectra Peaks of said protein by manipulating the coordinates of Table 1.

[0501] 92. A process for producing a medicament, pharmaceutical composition or drug, the process comprising: (a) identifying a BACE modulator molecule according to the method as defined in any one of paragraphs 73 to 79; (b) optimising the structure of the modulator molecule; and (c) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.

[0502] 93. A medicament, pharmaceutical composition or drug produced by, or obtainable by, the process of paragraph 92.

[0503] 94. A compound identified, produced or obtainable by the process or method of any one of paragraphs 73 to 79.

[0504] 95. A pharmaceutical composition, medicament, drug or other composition comprising the compound of paragraph 94.

[0505] 96. The medicament, pharmaceutical composition or drug of paragraph 93, compound of paragraph 94 or composition of paragraph 95 for use in medicine, for example for use in therapy or prophylaxis.

[0506] 97. The medicament, pharmaceutical composition, drug or composition of paragraph 96 wherein the therapy or prophylaxis comprises inhibiting BACE or the production of Aβ or fragments thereof or the treatment of Alzheimer's disease.

[0507] 98. A method of inhibiting BACE or the production of Aβ or fragments thereof or treating Alzheimer's disease comprising administering the miedicament, pharmaceutical composition, drug or composition of paragraph 96 to the patient.

[0508] 99. The method of paragraph 84, wherein the computer readable data is transmitted form the remove device.

[0509] 100. The method of paragraph 99, wherein the data is transmitted electronically or optically.

[0510] TABLE 1 ATOM 1 N PHE A 47p 65.730 61.598 −17.857 1.00 56.68 A N ATOM 2 CA PHE A 47p 66.426 61.383 −16.552 1.00 54.16 A C ATOM 3 C PHE A 47p 67.801 60.738 −16.734 1.00 54.30 A C ATOM 4 O PHE A 47p 68.258 59.983 −15.869 1.00 52.46 A O ATOM 5 CB PHE A 47p 65.566 60.500 −15.635 1.00 54.61 A C ATOM 6 CG PHE A 47p 64.161 61.008 −15.429 1.00 54.65 A C ATOM 7 CD1 PHE A 47p 63.110 60.508 −16.186 1.00 56.27 A C ATOM 8 CD2 PHE A 47p 63.887 61.970 −14.463 1.00 55.01 A C ATOM 9 CE1 PHE A 47p 61.812 60.972 −15.995 1.00 57.39 A C ATOM 10 CE2 PHE A 47p 62.596 62.435 −14.266 1.00 56.06 A C ATOM 11 CZ PHE A 47p 61.556 61.938 −15.035 1.00 56.47 A C ATOM 12 N VAL A 48p 68.468 61.048 −17.845 1.00 54.26 A N ATOM 13 CA VAL A 48p 69.737 60.395 −18.200 1.00 54.45 A C ATOM 14 C VAL A 48p 70.910 60.742 −17.276 1.00 53.21 A C ATOM 15 O VAL A 48p 71.847 59.947 −17.128 1.00 56.35 A O ATOM 16 CB VAL A 48p 70.156 60.691 −19.662 1.00 57.43 A C ATOM 17 CG1 VAL A 48p 69.222 59.972 −20.636 1.00 58.42 A C ATOM 18 CG2 VAL A 48p 70.204 62.208 −19.944 1.00 57.43 A C ATOM 19 N GLU A 1 70.860 61.925 −16.668 1.00 49.17 A N ATOM 20 CA GLU A 1 71.845 62.329 −15.674 1.00 46.84 A C ATOM 21 C GLU A 1 71.857 61.373 −14.479 1.00 42.66 A C ATOM 22 O GLU A 1 72.901 61.125 −13.891 1.00 45.10 A O ATOM 23 CB GLU A 1 71.532 63.740 −15.171 1.00 48.32 A C ATOM 24 CG GLU A 1 70.180 64.053 −14.545 0.00 50.15 A C ATOM 25 CD GLU A 1 68.942 64.394 −15.351 0.00 51.10 A C ATOM 26 OE1 GLU A 1 68.516 63.562 −16.178 0.00 51.29 A O ATOM 27 OE2 GLU A 1 68.395 65.500 −15.155 0.00 51.61 A O ATOM 28 N MET A 2 70.685 60.855 −14.125 1.00 37.18 A N ATOM 29 CA MET A 2 70.525 60.001 −12.942 1.00 32.72 A C ATOM 30 C MET A 2 70.875 58.531 −13.154 1.00 29.50 A C ATOM 31 O MET A 2 71.014 57.787 −12.183 1.00 29.19 A O ATOM 32 CB MET A 2 69.099 60.111 −12.415 1.00 30.14 A C ATOM 33 CG MET A 2 68.733 61.514 −12.005 1.00 34.84 A C ATOM 34 SD MET A 2 67.103 61.723 −11.322 1.00 36.26 A S ATOM 35 CE MET A 2 66.607 63.243 −12.134 1.00 40.05 A C ATOM 36 N VAL A 3 71.008 58.079 −14.396 1.00 28.21 A N ATOM 37 CA VAL A 3 71.291 56.669 −14.611 1.00 29.18 A C ATOM 38 C VAL A 3 72.690 56.364 −14.085 1.00 27.28 A C ATOM 39 O VAL A 3 73.622 57.149 −14.298 1.00 28.33 A O ATOM 40 CB VAL A 3 71.137 56.248 −16.094 1.00 32.19 A C ATOM 41 CG1 VAL A 3 71.649 54.826 −16.299 1.00 30.92 A C ATOM 42 CG2 VAL A 3 69.667 56.353 −16.525 1.00 32.71 A C ATOM 43 N ASP A 4 72.803 55.254 −13.359 1.00 28.19 A N ATOM 44 CA ASP A 4 74.066 54.739 −12.825 1.00 29.50 A C ATOM 45 C ASP A 4 74.600 55.632 −11.703 1.00 27.86 A C ATOM 46 O ASP A 4 75.797 55.682 −11.454 1.00 28.77 A O ATOM 47 CB ASP A 4 75.107 54.575 −13.940 1.00 32.06 A C ATOM 48 CG ASP A 4 76.254 53.655 −13.553 1.00 37.52 A C ATOM 49 OD1 ASP A 4 76.029 52.572 −12.945 1.00 38.24 A O ATOM 50 OD2 ASP A 4 77.438 53.952 −13.829 1.00 45.15 A O ATOM 51 N ASN A 5 73.694 56.308 −11.015 1.00 24.98 A N ATOM 52 CA ASN A 5 74.062 57.172 −9.876 1.00 18.95 A C ATOM 53 C ASN A 5 74.270 56.415 −8.544 1.00 22.40 A C ATOM 54 O ASN A 5 74.564 57.045 −7.515 1.00 21.31 A O ATOM 55 CB ASN A 5 73.064 58.329 −9.718 1.00 21.03 A C ATOM 56 CG ASN A 5 71.677 57.870 −9.366 1.00 16.73 A C ATOM 57 OD1 ASN A 5 71.424 56.673 −9.325 1.00 19.74 A O ATOM 58 ND2 ASN A 5 70.801 58.808 −9.035 1.00 21.06 A N ATOM 59 N LEU A 6 74.099 55.098 −8.562 1.00 15.94 A N ATOM 60 CA LEU A 6 74.323 54.236 −7.397 1.00 16.57 A C ATOM 61 C LEU A 6 75.531 53.321 −7.510 1.00 21.72 A C ATOM 62 O LEU A 6 75.855 52.780 −8.581 1.00 21.55 A O ATOM 63 CB LEU A 6 73.109 53.352 −7.078 1.00 18.17 A C ATOM 64 CG LEU A 6 71.707 53.957 −6.866 1.00 19.32 A C ATOM 65 CD1 LEU A 6 70.695 52.916 −6.521 1.00 17.46 A C ATOM 66 CD2 LEU A 6 71.748 54.997 −5.797 1.00 21.42 A C ATOM 67 N ARG A 7 76.173 53.126 −6.364 1.00 21.10 A N ATOM 68 CA ARG A 7 77.333 52.266 −6.230 1.00 23.84 A C ATOM 69 C ARG A 7 77.237 51.485 −4.939 1.00 25.78 A C ATOM 70 O ARG A 7 76.424 51.808 −4.059 1.00 21.54 A O ATOM 71 CB ARG A 7 78.610 53.103 −6.226 1.00 26.25 A C ATOM 72 CG ARG A 7 78.992 53.658 −7.583 1.00 30.55 A C ATOM 73 CD ARG A 7 80.135 54.652 −7.549 1.00 37.65 A C ATOM 74 NE ARG A 7 80.063 55.407 −8.932 0.00 40.50 A N ATOM 75 CZ ARG A 7 80.997 56.306 −9.222 0.00 41.92 A C ATOM 76 NH1 ARG A 7 80.991 56.911 −10.402 0.00 42.93 A N ATOM 77 NH2 ARG A 7 81.937 56.601 −8.335 0.00 42.80 A N ATOM 78 N GLY A 8 78.091 50.479 −4.799 1.00 26.16 A N ATOM 79 CA GLY A 8 78.086 49.663 −3.598 1.00 29.54 A C ATOM 80 C GLY A 8 79.032 48.490 −3.639 1.00 31.18 A C ATOM 81 O GLY A 8 79.790 48.325 −4.591 1.00 33.68 A O ATOM 82 N LYS A 9 78.986 47.685 −2.587 1.00 34.88 A N ATOM 83 CA LYS A 9 79.643 48.390 −2.578 1.00 36.27 A C ATOM 84 C LYS A 9 78.625 45.337 −2.169 1.00 37.50 A C ATOM 85 O LYS A 9 77.771 45.576 −1.316 1.00 32.87 A O ATOM 86 CB LYS A 9 80.861 46.396 −1.649 1.00 39.66 A C ATOM 87 CG LYS A 9 81.975 47.324 −2.120 1.00 45.29 A C ATOM 88 CD LYS A 9 83.346 46.635 −2.207 1.00 50.21 A C ATOM 89 CE LYS A 9 84.382 47.543 −2.887 1.00 52.01 A C ATOM 90 NZ LYS A 9 85.408 48.085 −1.943 1.00 53.23 A N ATOM 91 N SER A 10 78.708 44.172 −2.805 1.00 38.65 A N ATOM 92 CA SER A 10 77.807 43.063 −2.525 1.00 39.77 A C ATOM 93 C SER A 10 77.658 42.852 −1.026 1.00 38.92 A C ATOM 94 O SER A 10 78.658 42.718 −0.316 1.00 38.89 A O ATOM 95 CB SER A 10 78.336 41.776 −3.172 1.00 41.88 A C ATOM 96 OG SER A 10 77.485 40.680 −2.879 1.00 44.59 A O ATOM 97 N GLY A 11 76.410 42.857 −0.556 1.00 36.41 A N ATOM 98 CA GLY A 11 76.097 42.627 0.843 1.00 35.71 A C ATOM 99 C GLY A 11 76.076 43.859 1.738 1.00 35.38 A C ATOM 100 O GLY A 11 75.631 43.757 2.886 1.00 37.81 A O ATOM 101 N GLN A 12 76.519 45.005 1.213 1.00 34.18 A N ATOM 102 CA GLN A 12 76.732 46.234 1.999 1.00 35.64 A C ATOM 103 C GLN A 12 75.861 47.409 1.536 1.00 35.07 A C ATOM 104 O GLN A 12 76.148 48.558 1.881 1.00 36.40 A O ATOM 105 CB GLN A 12 78.196 46.693 1.913 1.00 37.52 A C ATOM 106 CG GLN A 12 79.230 45.703 2.437 1.00 42.55 A C ATOM 107 CD GLN A 12 80.653 46.267 2.465 1.00 40.98 A C ATOM 108 OE1 GLN A 12 81.562 45.623 2.984 1.00 49.77 A O ATOM 109 NE2 GLN A 12 80.846 47.450 1.904 1.00 50.11 A N ATOM 110 N GLY A 13 74.824 47.132 0.749 1.00 30.97 A N ATOM 111 CA GLY A 13 73.887 48.163 0.331 1.00 27.55 A C ATOM 112 C GLY A 13 74.366 49.021 −0.820 1.00 25.65 A C ATOM 113 O GLY A 13 75.491 48.904 −1.289 1.00 26.10 A O ATOM 114 N TYR A 14 73.477 49.892 −1.275 1.00 17.01 A N ATOM 115 CA TYR A 14 73.738 50.794 −2.395 1.00 17.38 A C ATOM 116 C TYR A 14 73.722 52.218 −1.880 1.00 16.80 A C ATOM 117 O TYR A 14 72.851 52.561 −1.072 1.00 17.47 A O ATOM 118 CB TYR A 14 72.635 50.663 −3.446 1.00 18.29 A C ATOM 119 CG TYR A 14 72.651 49.339 −4.162 1.00 21.45 A C ATOM 120 CD1 TYR A 14 72.134 48.194 −3.574 1.00 20.72 A C ATOM 121 CD2 TYR A 14 73.201 49.239 −5.434 1.00 21.04 A C ATOM 122 CE1 TYR A 14 72.164 46.981 −4.246 1.00 20.87 A C ATOM 123 CE2 TYR A 14 73.233 48.043 −6.101 1.00 23.36 A C ATOM 124 CZ TYR A 14 72.723 46.935 −5.522 1.00 24.50 A C ATOM 125 OH TYR A 14 72.758 45.757 −6.229 1.00 27.32 A O ATOM 126 N TYR A 15 74.636 53.044 −2.387 1.00 18.15 A N ATOM 127 CA TYR A 15 74.727 54.431 −1.976 1.00 15.54 A C ATOM 128 C TYR A 15 74.734 55.415 −3.133 1.00 16.89 A C ATOM 129 O TYR A 15 75.171 55.108 −4.243 1.00 17.87 A O ATOM 130 CB TYR A 15 75.951 54.666 −1.064 1.00 16.46 A C ATOM 131 CG TYR A 15 77.308 54.342 −1.685 1.00 15.58 A C ATOM 132 CD1 TYR A 15 77.966 55.246 −2.501 1.00 19.48 A C ATOM 133 CD2 TYR A 15 77.919 53.139 −1.411 1.00 19.60 A C ATOM 134 CE1 TYR A 15 79.201 54.956 −3.034 1.00 21.95 A C ATOM 135 CE2 TYR A 15 79.165 52.838 −1.926 1.00 23.26 A C ATOM 136 CZ TYR A 15 79.787 53.734 −2.739 1.00 21.80 A C ATOM 137 OH TYR A 15 81.006 53.396 −3.255 1.00 26.17 A O ATOM 138 N VAL A 16 74.279 56.620 −2.823 1.00 17.50 A N ATOM 139 CA VAL A 16 74.197 57.728 −3.760 1.00 19.34 A C ATOM 140 C VAL A 16 75.077 58.862 −3.212 1.00 20.35 A C ATOM 141 O VAL A 16 75.165 59.056 −1.995 1.00 29.27 A O ATOM 142 CB VAL A 16 72.715 58.201 −3.936 1.00 18.58 A C ATOM 143 CG1 VAL A 16 72.177 58.911 −2.680 1.00 18.67 A C ATOM 144 CG2 VAL A 16 72.554 59.101 −5.172 1.00 21.03 A C ATOM 145 N GLU A 17 75.715 59.608 −4.101 1.00 20.07 A N ATOM 146 CA GLU A 17 76.401 60.838 −3.706 1.00 22.44 A C ATOM 147 C GLU A 17 75.398 61.943 −3.372 1.00 22.83 A C ATOM 148 O GLU A 17 74.419 62.145 −4.091 1.00 20.94 A O ATOM 149 CB GLU A 17 77.360 61.298 −4.810 1.00 23.72 A C ATOM 150 CG GLU A 17 78.246 62.482 −4.416 1.00 28.53 A C ATOM 151 CD GLU A 17 79.065 63.024 −5.580 1.00 36.53 A C ATOM 152 OE1 GLU A 17 78.956 64.228 −5.878 1.00 39.02 A O ATOM 153 OE2 GLU A 17 79.820 62.249 −6.201 1.00 41.99 A O ATOM 154 N MET A 18 75.616 62.632 −2.249 1.00 18.64 A N ATOM 155 CA MET A 18 74.824 63.788 −1.849 1.00 18.78 A C ATOM 156 C MET A 18 75.744 64.904 −1.365 1.00 24.24 A C ATOM 157 O MET A 18 76.919 64.671 −1.079 1.00 23.12 A O ATOM 158 CB MET A 18 73.866 63.427 −0.717 1.00 20.09 A C ATOM 159 CG MET A 18 72.884 62.284 −1.064 1.00 17.91 A C ATOM 160 SD MET A 18 71.685 61.911 0.240 1.00 20.92 A S ATOM 161 CE MET A 18 70.491 63.197 −0.005 1.00 21.35 A C ATOM 162 N THR A 19 75.229 66.121 −1.313 1.00 24.86 A N ATOM 163 CA THR A 19 75.966 67.206 −0.661 1.00 26.57 A C ATOM 164 C THR A 19 75.122 67.794 0.443 1.00 24.45 A C ATOM 165 O THR A 19 73.904 67.861 0.341 1.00 23.60 A O ATOM 166 CB THR A 19 76.392 68.292 −1.665 1.00 28.59 A C ATOM 167 OG1 THR A 19 75.236 68.833 −2.311 1.00 32.78 A O ATOM 168 CG2 THR A 19 77.235 67.712 −2.775 1.00 28.11 A C ATOM 169 N VAL A 20 75.775 68.213 1.531 1.00 25.61 A N ATOM 170 CA VAL A 20 75.078 68.836 2.643 1.00 22.00 A C ATOM 171 C VAL A 20 75.826 70.130 2.995 1.00 21.90 A C ATOM 172 O VAL A 20 77.040 70.183 2.841 1.00 23.44 A O ATOM 173 CB VAL A 20 75.011 67.902 3.848 1.00 25.28 A C ATOM 174 CG1 VAL A 20 74.361 68.579 5.033 1.00 30.83 A C ATOM 175 CG2 VAL A 20 74.245 66.611 3.495 1.00 25.14 A C ATOM 176 N GLY A 21 75.077 71.146 3.422 1.00 25.14 A N ATOM 177 CA GLY A 21 75.623 72.434 3.837 1.00 27.79 A C ATOM 178 C GLY A 21 76.015 73.417 2.752 1.00 26.88 A C ATOM 179 O GLY A 21 75.906 73.137 1.551 1.00 27.40 A O ATOM 180 N SER A 22 76.466 74.594 3.202 1.00 28.28 A N ATOM 181 CA SER A 22 76.976 75.657 2.330 1.00 29.16 A C ATOM 182 C SER A 22 78.298 76.173 2.919 1.00 28.62 A C ATOM 183 O SER A 22 78.308 76.639 4.049 1.00 29.95 A O ATOM 184 CB SER A 22 75.983 76.815 2.238 1.00 29.69 A C ATOM 185 OG SER A 22 74.675 76.366 1.925 1.00 29.77 A O ATOM 186 N PRO A 23 79.407 76.052 2.198 1.00 28.22 A N ATOM 187 CA PRO A 23 79.461 75.401 0.884 1.00 30.78 A C ATOM 188 C PRO A 23 79.227 73.886 0.976 1.00 29.87 A C ATOM 189 O PRO A 23 79.338 73.300 2.063 1.00 25.45 A O ATOM 190 CB PRO A 23 80.875 75.693 0.407 1.00 31.63 A C ATOM 191 CG PRO A 23 81.664 75.968 1.651 1.00 29.94 A C ATOM 192 CD PRO A 23 80.727 76.545 2.629 1.00 33.02 A C ATOM 193 N PRO A 24 78.894 73.258 −0.145 1.00 30.31 A N ATOM 194 CA PRO A 24 78.559 71.821 −0.139 1.00 26.63 A C ATOM 195 C PRO A 24 79.673 70.857 0.304 1.00 25.38 A C ATOM 196 O PRO A 24 80.807 70.925 −0.155 1.00 25.17 A O ATOM 197 CB PRO A 24 78.141 71.536 −1.593 1.00 28.22 A C ATOM 198 CG PRO A 24 78.576 72.715 −2.410 1.00 32.40 A C ATOM 199 CD PRO A 24 78.778 73.874 −1.484 1.00 33.13 A C ATOM 200 N GLN A 25 79.292 69.920 1.169 1.00 24.26 A N ATOM 201 CA GLN A 25 80.144 68.839 1.620 1.00 23.05 A C ATOM 202 C GLN A 25 79.617 67.576 0.992 1.00 19.90 A C ATOM 203 O GLN A 25 78.470 67.220 1.220 1.00 20.87 A O ATOM 204 CB GLN A 25 80.075 68.728 3.127 1.00 20.92 A C ATOM 205 CG GLN A 25 80.581 69.995 3.817 1.00 25.92 A C ATOM 206 CD GLN A 25 80.491 69.911 5.317 1.00 24.91 A C ATOM 207 OE1 GLN A 25 80.742 68.850 5.894 1.00 21.17 A O ATOM 208 NE2 GLN A 25 80.153 71.021 5.957 1.00 26.06 A N ATOM 209 N THR A 26 80.439 66.926 0.187 1.00 23.72 A N ATOM 210 CA THR A 26 80.041 65.699 −0.495 1.00 23.00 A C ATOM 211 C THR A 26 80.141 64.498 0.435 1.00 22.59 A C ATOM 212 O THR A 26 81.151 64.310 1.103 1.00 23.44 A O ATOM 213 CB THR A 26 80.943 65.456 −1.685 1.00 24.91 A C ATOM 214 OG1 THR A 26 80.891 66.588 −2.566 1.00 31.54 A O ATOM 215 CG2 THR A 26 80.428 64.292 −2.537 1.00 25.28 A C ATOM 216 N LEU A 27 79.107 63.666 0.430 1.00 19.15 A N ATOM 217 CA LEU A 27 79.093 62.431 1.198 1.00 18.03 A C ATOM 218 C LEU A 27 78.394 61.329 0.375 1.00 22.50 A C ATOM 219 O LEU A 27 77.511 61.636 −0.415 1.00 25.14 A O ATOM 220 CB LEU A 27 78.310 62.637 2.488 1.00 18.41 A C ATOM 221 CG LEU A 27 78.805 63.740 3.447 1.00 23.17 A C ATOM 222 CD1 LEU A 27 77.737 64.155 4.429 1.00 28.47 A C ATOM 223 CD2 LEU A 27 80.040 63.300 4.174 1.00 22.35 A C ATOM 224 N ASN A 28 78.804 60.075 0.562 1.00 19.63 A N ATOM 225 CA ASN A 28 78.097 58.926 −0.013 1.00 18.44 A C ATOM 226 C ASN A 28 77.098 58.404 0.985 1.00 17.41 A C ATOM 227 O ASN A 28 77.467 58.130 2.122 1.00 15.99 A O ATOM 228 CB ASN A 28 79.059 57.817 −0.346 1.00 17.43 A C ATOM 229 CG ASN A 28 79.868 58.114 −1.556 1.00 22.09 A C ATOM 230 OD1 ASN A 28 79.407 58.837 −2.434 1.00 21.00 A O ATOM 231 ND2 ASN A 28 81.084 57.573 −1.622 1.00 22.09 A N ATOM 232 N ILE A 29 75.848 58.222 0.566 1.00 13.33 A N ATOM 233 CA ILE A 29 74.741 57.964 1.501 1.00 15.06 A C ATOM 234 C ILE A 29 73.969 56.724 1.072 1.00 15.98 A C ATOM 235 O ILE A 29 73.495 56.628 −0.071 1.00 16.00 A O ATOM 236 CB ILE A 29 73.777 59.164 1.569 1.00 17.19 A C ATOM 237 CG1 ILE A 29 74.533 60.443 1.960 1.00 16.84 A C ATOM 238 CG2 ILE A 29 72.625 58.876 2.579 1.00 15.77 A C ATOM 239 CD1 ILE A 29 75.147 60.409 3.359 1.00 18.72 A C ATOM 240 N LEU A 30 73.829 55.787 1.997 1.00 15.17 A N ATOM 241 CA LEU A 30 73.110 54.541 1.743 1.00 16.63 A C ATOM 242 C LEU A 30 71.623 54.825 1.455 1.00 17.89 A C ATOM 243 O LEU A 30 71.000 55.542 2.186 1.00 17.80 A O ATOM 244 CB LEU A 30 73.251 53.629 2.964 1.00 14.92 A C ATOM 245 CG LEU A 30 72.441 52.335 2.947 1.00 24.85 A C ATOM 246 CD1 LEU A 30 73.456 51.336 1.962 0.00 19.90 A C ATOM 247 CD2 LEU A 30 72.418 51.625 4.210 0.00 19.96 A C ATOM 248 N VAL A 31 71.059 54.224 0.405 1.00 15.67 A N ATOM 249 CA VAL A 31 69.656 54.390 0.066 1.00 17.96 A C ATOM 250 C VAL A 31 68.865 53.269 0.715 1.00 18.65 A C ATOM 251 O VAL A 31 69.101 52.060 0.440 1.00 21.01 A O ATOM 252 CB VAL A 31 69.461 54.358 −1.471 1.00 21.10 A C ATOM 253 CG1 VAL A 31 67.991 54.309 −1.806 1.00 23.22 A C ATOM 254 CG2 VAL A 31 70.102 55.554 −2.073 1.00 19.69 A C ATOM 255 N ASP A 32 67.936 53.656 1.591 1.00 18.25 A N ATOM 256 CA ASP A 32 67.221 52.712 2.456 1.00 20.14 A C ATOM 257 C ASP A 32 65.712 52.942 2.457 1.00 18.89 A C ATOM 258 O ASP A 32 65.217 53.839 3.144 1.00 18.73 A O ATOM 259 CB ASP A 32 67.748 52.832 3.905 1.00 20.81 A C ATOM 260 CG ASP A 32 67.163 51.747 4.850 1.00 27.29 A C ATOM 261 OD1 ASP A 32 66.652 50.729 4.345 1.00 28.02 A O ATOM 262 OD2 ASP A 32 67.178 51.817 6.113 1.00 29.94 A O ATOM 263 N THR A 33 64.947 52.108 1.735 1.00 15.71 A N ATOM 264 CA THR A 33 63.500 52.284 1.753 1.00 16.65 A C ATOM 265 C THR A 33 62.839 51.643 2.958 1.00 18.62 A C ATOM 266 O THR A 33 61.627 51.707 3.086 1.00 19.27 A O ATOM 267 CB THR A 33 62.855 51.726 0.459 1.00 17.78 A C ATOM 268 OG1 THR A 33 63.088 50.330 0.395 1.00 17.76 A O ATOM 269 CG2 THR A 33 63.526 52.289 −0.756 1.00 20.47 A C ATOM 270 N GLY A 34 63.645 51.078 3.854 1.00 19.46 A N ATOM 271 CA GLY A 34 63.137 50.457 5.065 1.00 22.82 A C ATOM 272 C GLY A 34 63.251 51.314 6.315 1.00 24.98 A C ATOM 273 O GLY A 34 63.033 50.830 7.434 1.00 24.60 A O ATOM 274 N SER A 35 63.601 52.578 6.130 1.00 18.89 A N ATOM 275 CA SER A 35 63.672 53.543 7.231 1.00 21.21 A C ATOM 276 C SER A 35 63.376 54.978 6.749 1.00 18.57 A C ATOM 277 O SER A 35 63.245 55.229 5.535 1.00 21.32 A O ATOM 278 CB SER A 35 65.045 53.420 7.880 1.00 21.69 A C ATOM 279 OG SER A 35 66.063 53.982 7.078 1.00 20.28 A O ATOM 280 N SER A 36 63.253 55.940 7.678 1.00 18.30 A N ATOM 281 CA SER A 36 62.727 57.267 7.347 1.00 20.36 A C ATOM 282 C SER A 36 63.545 58.455 7.889 1.00 21.41 A C ATOM 283 O SER A 36 63.101 59.594 7.809 1.00 19.92 A O ATOM 284 CB SER A 36 61.267 57.375 7.824 1.00 25.82 A C ATOM 285 OG SER A 36 60.485 56.344 7.230 1.00 25.30 A O ATOM 286 N ASN A 37 64.748 58.181 8.396 1.00 19.59 A N ATOM 287 CA ASN A 37 65.676 59.222 8.853 1.00 20.44 A C ATOM 288 C ASN A 37 66.852 59.444 7.907 1.00 17.40 A C ATOM 289 O ASN A 37 67.426 58.484 7.386 1.00 17.40 A O ATOM 290 CB ASN A 37 66.262 58.847 10.225 1.00 19.75 A C ATOM 291 CG ASN A 37 65.330 59.162 11.365 1.00 25.09 A C ATOM 292 OD1 ASN A 37 65.323 60.288 11.888 1.00 26.01 A O ATOM 293 ND2 ASN A 37 64.555 58.177 11.776 1.00 21.61 A N ATOM 294 N PHE A 38 67.217 60.704 7.697 1.00 18.60 A N ATOM 295 CA PHE A 38 68.450 61.064 7.013 1.00 17.76 A C ATOM 296 C PHE A 38 69.494 61.330 8.089 1.00 17.46 A C ATOM 297 O PHE A 38 69.356 62.288 8.837 1.00 18.26 A O ATOM 298 CB PHE A 38 68.236 62.307 6.143 1.00 17.46 A C ATOM 299 CG PHE A 38 69.466 62.776 5.366 1.00 18.60 A C ATOM 300 CD1 PHE A 38 70.391 61.896 4.828 1.00 17.37 A C ATOM 301 CD2 PHE A 38 69.657 64.124 5.127 1.00 24.93 A C ATOM 302 CE1 PHE A 38 71.488 62.350 4.104 1.00 19.65 A C ATOM 303 CE2 PHE A 38 70.747 64.586 4.384 1.00 19.49 A C ATOM 304 CZ PHE A 38 71.669 63.701 3.881 1.00 23.24 A C ATOM 305 N ALA A 39 70.467 60.430 8.224 1.00 18.71 A N ATOM 306 CA ALA A 39 71.480 60.508 9.272 1.00 18.80 A C ATOM 307 C ALA A 39 72.866 60.348 8.667 1.00 20.90 A C ATOM 308 O ALA A 39 73.104 59.439 7.862 1.00 20.32 A O ATOM 309 CB ALA A 39 71.225 59.457 10.334 1.00 17.93 A C ATOM 310 N VAL A 40 73.792 61.223 9.058 1.00 19.20 A N ATOM 311 CA VAL A 40 75.145 61.189 8.526 1.00 18.03 A C ATOM 312 C VAL A 40 76.193 61.242 9.640 1.00 18.42 A C ATOM 313 O VAL A 40 76.027 61.985 10.580 1.00 15.83 A O ATOM 314 CB VAL A 40 75.398 62.372 7.587 1.00 19.32 A C ATOM 315 CG1 VAL A 40 74.430 62.354 6.382 1.00 24.72 A C ATOM 316 CG2 VAL A 40 75.304 63.711 8.319 1.00 25.33 A C ATOM 317 N GLY A 41 77.272 60.490 9.488 1.00 18.41 A N ATOM 318 CA GLY A 41 78.444 60.626 10.354 1.00 13.03 A C ATOM 319 C GLY A 41 78.921 62.049 10.463 1.00 16.57 A C ATOM 320 O GLY A 41 78.986 62.780 9.486 1.00 16.35 A O ATOM 321 N ALA A 42 79.186 62.482 11.688 1.00 18.46 A N ATOM 322 CA ALA A 42 79.513 63.880 11.952 1.00 16.09 A C ATOM 323 C ALA A 42 80.745 63.987 12.843 1.00 21.94 A C ATOM 324 O ALA A 42 81.068 65.059 13.334 1.00 21.99 A O ATOM 325 CB ALA A 42 78.326 64.558 12.613 1.00 19.21 A C ATOM 326 N ALA A 43 81.444 62.873 12.985 1.00 17.43 A N ATOM 327 CA ALA A 43 82.584 62.752 13.899 1.00 19.03 A C ATOM 328 C ALA A 43 83.590 61.822 13.222 1.00 22.11 A C ATOM 329 O ALA A 43 83.186 60.977 12.414 1.00 18.84 A O ATOM 330 CB ALA A 43 82.131 62.185 15.216 1.00 20.66 A C ATOM 331 N PRO A 44 84.880 61.964 13.530 1.00 21.75 A N ATOM 332 CA PRO A 44 85.928 61.128 12.903 1.00 22.99 A C ATOM 333 C PRO A 44 86.039 59.692 13.422 1.00 21.03 A C ATOM 334 O PRO A 44 87.044 59.283 13.989 1.00 22.42 A O ATOM 335 CB PRO A 44 87.204 61.930 13.173 1.00 23.97 A C ATOM 336 CG PRO A 44 86.923 62.655 14.467 1.00 21.28 A C ATOM 337 CD PRO A 44 85.466 63.000 14.406 1.00 22.65 A C ATOM 338 N HIS A 45 85.004 58.904 13.175 1.00 19.15 A N ATOM 339 CA HIS A 45 85.011 57.491 13.493 1.00 19.87 A C ATOM 340 C HIS A 45 86.074 56.884 12.559 1.00 23.49 A C ATOM 341 O HIS A 45 86.161 57.279 11.408 1.00 18.76 A O ATOM 342 CB HIS A 45 83.600 56.898 13.231 1.00 20.18 A C ATOM 343 CG HIS A 45 83.499 55.426 13.491 1.00 20.56 A C ATOM 344 ND1 HIS A 45 82.921 54.900 14.628 1.00 27.21 A N ATOM 345 CD2 HIS A 45 83.911 54.369 12.753 1.00 20.97 A C ATOM 346 CE1 HIS A 45 82.989 53.579 14.577 1.00 20.15 A C ATOM 347 NE2 HIS A 45 83.572 53.234 13.443 1.00 26.79 A N ATOM 348 N PRO A 46 86.900 55.958 13.039 1.00 23.59 A N ATOM 349 CA PRO A 46 87.999 55.418 12.221 1.00 26.27 A C ATOM 350 C PRO A 46 87.618 54.722 10.881 1.00 23.39 A C ATOM 351 O PRO A 46 88.449 54.679 9.975 1.00 27.08 A O ATOM 352 CB PRO A 46 88.677 54.416 13.175 1.00 24.42 A C ATOM 353 CG PRO A 46 87.621 54.034 14.147 1.00 27.39 A C ATOM 354 CD PRO A 46 86.863 55.335 14.378 1.00 25.05 A C ATOM 355 N PHE A 47 86.410 54.192 10.783 1.00 25.26 A N ATOM 356 CA PHE A 47 85.924 53.538 9.560 1.00 25.03 A C ATOM 357 C PHE A 47 85.523 54.517 8.446 1.00 22.84 A C ATOM 358 O PHE A 47 85.309 54.084 7.325 1.00 25.36 A O ATOM 359 CB PHE A 47 84.678 52.671 9.832 1.00 27.84 A C ATOM 360 CG PHE A 47 84.888 51.503 10.769 1.00 32.30 A C ATOM 361 CD1 PHE A 47 86.141 51.176 11.282 1.00 36.05 A C ATOM 362 CD2 PHE A 47 83.794 50.722 11.134 1.00 35.59 A C ATOM 363 CE1 PHE A 47 86.297 50.098 12.133 1.00 32.80 A C ATOM 364 CE2 PHE A 47 83.945 49.635 12.004 1.00 36.20 A C ATOM 365 CZ PHE A 47 85.197 49.326 12.489 1.00 37.31 A C ATOM 366 N LEU A 48 85.377 55.804 8.761 1.00 19.13 A N ATOM 367 CA LEU A 48 84.818 56.789 7.835 1.00 18.71 A C ATOM 368 C LEU A 48 85.829 57.499 6.963 1.00 22.04 A C ATOM 369 O LEU A 48 86.798 58.086 7.451 1.00 22.43 A O ATOM 370 CB LEU A 48 84.019 57.848 8.602 1.00 17.69 A C ATOM 371 CG LEU A 48 82.797 57.361 9.367 1.00 14.97 A C ATOM 372 CD1 LEU A 48 82.068 58.567 9.926 1.00 18.29 A C ATOM 373 CD2 LEU A 48 81.839 56.567 8.517 1.00 19.80 A C ATOM 374 N HIS A 49 85.553 57.517 5.666 1.00 19.90 A N ATOM 375 CA HIS A 49 86.310 58.348 4.715 1.00 23.16 A C ATOM 376 C HIS A 49 86.115 59.862 4.903 1.00 23.74 A C ATOM 377 O HIS A 49 87.033 60.658 4.676 1.00 24.96 A O ATOM 378 CB HIS A 49 85.901 58.027 3.277 1.00 24.78 A C ATOM 379 CG HIS A 49 86.253 56.648 2.822 1.00 18.81 A C ATOM 380 ND1 HIS A 49 87.368 56.386 2.054 1.00 23.64 A N ATOM 381 CD2 HIS A 49 85.623 55.463 2.989 1.00 17.53 A C ATOM 382 CE1 HIS A 49 87.408 55.095 1.779 1.00 20.49 A C ATOM 383 NE2 HIS A 49 86.361 54.512 2.331 1.00 25.00 A N ATOM 384 N ARG A 50 84.900 60.274 5.255 1.00 23.13 A N ATOM 385 CA ARG A 50 84.603 61.682 5.496 1.00 24.92 A C ATOM 386 C ARG A 50 83.387 61.768 6.398 1.00 22.50 A C ATOM 387 O ARG A 50 82.761 60.763 6.692 1.00 20.11 A O ATOM 388 CB ARG A 50 84.335 62.435 4.200 1.00 31.00 A C ATOM 389 CG ARG A 50 84.028 61.549 3.065 1.00 30.52 A C ATOM 390 CD ARG A 50 83.871 62.231 1.758 1.00 33.45 A C ATOM 391 NE ARG A 50 83.103 61.374 0.862 1.00 35.30 A N ATOM 392 CZ ARG A 50 82.912 61.613 −0.430 1.00 41.98 A C ATOM 393 NH1 ARG A 50 83.440 62.692 −1.000 1.00 41.62 A N ATOM 394 NH2 ARG A 50 82.188 60.765 −1.159 1.00 41.63 A N ATOM 395 N TYR A 51 83.097 62.978 6.868 1.00 19.69 A N ATOM 396 CA TYR A 51 81.968 63.193 7.727 1.00 19.01 A C ATOM 397 C TYR A 51 81.513 64.641 7.644 1.00 17.45 A C ATOM 398 O TYR A 51 82.257 65.509 7.198 1.00 19.82 A O ATOM 399 CB TYR A 51 82.305 62.792 9.175 1.00 17.00 A C ATOM 400 CG TYR A 51 83.594 63.414 9.694 1.00 19.81 A C ATOM 401 CD1 TYR A 51 84.807 62.799 9.494 1.00 22.49 A C ATOM 402 CD2 TYR A 51 83.574 64.625 10.391 1.00 27.51 A C ATOM 403 CE1 TYR A 51 85.996 63.363 9.962 1.00 29.01 A C ATOM 404 CE2 TYR A 51 84.755 65.198 10.853 1.00 22.34 A C ATOM 405 CZ TYR A 51 85.959 64.561 10.639 1.00 26.38 A C ATOM 406 OH TYR A 51 87.153 65.103 11.102 1.00 27.75 A O ATOM 407 N TYR A 52 80.267 64.861 8.039 1.00 16.76 A N ATOM 408 CA TYR A 52 79.630 66.167 8.044 1.00 15.41 A C ATOM 409 C TYR A 52 80.251 67.057 9.094 1.00 18.19 A C ATOM 410 O TYR A 52 80.252 66.703 10.268 1.00 18.86 A O ATOM 411 CB TYR A 52 78.163 65.968 8.360 1.00 16.96 A C ATOM 412 CG TYR A 52 77.241 67.158 8.365 1.00 17.78 A C ATOM 413 CD1 TYR A 52 77.491 68.311 7.617 1.00 19.54 A C ATOM 414 CD2 TYR A 52 76.057 67.095 9.075 1.00 20.48 A C ATOM 415 CE1 TYR A 52 76.608 69.378 7.664 1.00 17.41 A C ATOM 416 CE2 TYR A 52 75.160 68.137 9.089 1.00 21.75 A C ATOM 417 CZ TYR A 52 75.443 69.280 8.373 1.00 20.07 A C ATOM 418 OH TYR A 52 74.507 70.291 8.424 1.00 24.27 A O ATOM 419 N GLN A 53 80.748 68.214 8.671 1.00 21.06 A N ATOM 420 CA GLN A 53 81.372 69.186 9.580 1.00 22.83 A C ATOM 421 C GLN A 53 80.474 70.420 9.662 1.00 18.33 A C ATOM 422 O GLN A 53 80.601 71.340 8.878 1.00 23.76 A O ATOM 423 CB GLN A 53 82.779 69.535 9.079 1.00 22.30 A C ATOM 424 CG GLN A 53 83.750 68.353 9.108 1.00 24.84 A C ATOM 425 CD GLN A 53 85.187 68.690 8.695 1.00 31.20 A C ATOM 426 OE1 GLN A 53 85.490 68.915 7.504 1.00 32.31 A O ATOM 427 NE2 GLN A 53 86.080 68.696 9.671 1.00 27.07 A N ATOM 428 N ARG A 54 79.537 70.385 10.597 1.00 20.86 A N ATOM 429 CA ARG A 54 78.545 71.442 10.758 1.00 21.52 A C ATOM 430 C ARG A 54 79.164 72.827 10.939 1.00 25.15 A C ATOM 431 O ARG A 54 78.568 73.828 10.536 1.00 26.20 A O ATOM 432 CB ARG A 54 77.629 71.138 11.918 1.00 21.46 A C ATOM 433 CG ARG A 54 76.652 69.995 11.655 1.00 22.36 A C ATOM 434 CD ARG A 54 75.989 69.437 12.869 1.00 24.51 A C ATOM 435 NE ARG A 54 76.919 68.779 13.780 1.00 20.24 A N ATOM 436 CZ ARG A 54 76.609 68.376 14.997 1.00 23.34 A C ATOM 437 NH1 ARG A 54 75.389 68.574 15.485 1.00 26.99 A N ATOM 438 NH2 ARG A 54 77.534 67.786 15.739 1.00 21.22 A N ATOM 439 N GLN A 55 80.362 72.880 11.523 1.00 25.18 A N ATOM 440 CA GLN A 55 81.055 74.153 11.741 1.00 25.49 A C ATOM 441 C GLN A 55 81.403 74.886 10.453 1.00 27.22 A C ATOM 442 O GLN A 55 81.623 76.106 10.471 1.00 31.96 A O ATOM 443 CB GLN A 55 82.342 73.951 12.586 1.00 25.44 A C ATOM 444 CG GLN A 55 83.508 73.285 11.866 1.00 26.87 A C ATOM 445 CD GLN A 55 83.607 71.787 12.100 1.00 22.47 A C ATOM 446 OE1 GLN A 55 84.649 71.186 11.858 1.00 28.14 A O ATOM 447 NE2 GLN A 55 82.531 71.192 12.526 1.00 19.06 A N ATOM 448 N LEU A 56 81.478 74.148 9.347 1.00 26.29 A N ATOM 449 CA LEU A 56 81.846 74.711 8.055 1.00 26.09 A C ATOM 450 C LEU A 56 80.646 75.193 7.224 1.00 28.01 A C ATOM 451 O LEU A 56 80.835 75.716 6.131 1.00 30.64 A O ATOM 452 CB LEU A 56 82.667 73.703 7.251 1.00 28.42 A C ATOM 453 CG LEU A 56 83.966 73.147 7.849 1.00 29.81 A C ATOM 454 CD1 LEU A 56 84.685 72.309 6.814 1.00 33.56 A C ATOM 455 CD2 LEU A 56 84.896 74.243 8.364 1.00 28.02 A C ATOM 456 N SER A 57 79.432 75.055 7.760 1.00 27.95 A N ATOM 457 CA SER A 57 78.199 75.322 7.009 1.00 27.26 A C ATOM 458 C SER A 57 77.432 76.528 7.548 1.00 26.45 A C ATOM 459 O SER A 57 76.970 76.523 8.701 1.00 27.40 A O ATOM 460 CB SER A 57 77.287 74.086 7.037 1.00 27.30 A C ATOM 461 OG SER A 57 76.004 74.353 6.482 1.00 24.82 A O ATOM 462 N SER A 58 77.250 77.541 6.704 1.00 31.30 A N ATOM 463 CA SER A 58 76.540 78.753 7.112 1.00 33.18 A C ATOM 464 C SER A 58 75.049 78.502 7.294 1.00 33.96 A C ATOM 465 O SER A 58 74.367 79.198 8.059 1.00 31.39 A O ATOM 466 CB SER A 58 76.761 79.879 6.097 1.00 35.14 A C ATOM 467 OG SER A 58 76.449 79.481 4.769 1.00 35.98 A O ATOM 468 N THR A 59 74.552 77.473 6.608 1.00 31.44 A N ATOM 469 CA THR A 59 73.128 77.222 6.528 1.00 28.82 A C ATOM 470 C THR A 59 72.637 76.209 7.545 1.00 27.75 A C ATOM 471 O THR A 59 71.431 75.989 7.648 1.00 26.38 A O ATOM 472 CB THR A 59 72.745 76.825 5.079 1.00 30.74 A C ATOM 473 OG1 THR A 59 73.712 75.937 4.512 1.00 26.79 A O ATOM 474 CG2 THR A 59 72.851 78.040 4.175 1.00 31.50 A C ATOM 475 N TYR A 60 73.559 75.630 8.325 1.00 25.76 A N ATOM 476 CA TYR A 60 73.204 74.716 9.405 1.00 27.01 A C ATOM 477 C TYR A 60 72.359 75.391 10.487 1.00 30.17 A C ATOM 478 O TYR A 60 72.671 76.504 10.908 1.00 32.85 A O ATOM 479 CB TYR A 60 74.475 74.108 10.024 1.00 29.24 A C ATOM 480 CG TYR A 60 74.208 73.401 11.319 1.00 32.58 A C ATOM 481 CD1 TYR A 60 73.616 72.137 11.341 1.00 33.45 A C ATOM 482 CD2 TYR A 60 74.507 74.016 12.539 1.00 35.22 A C ATOM 483 CE1 TYR A 60 73.344 71.495 12.545 1.00 34.91 A C ATOM 484 CE2 TYR A 60 74.242 73.384 13.741 1.00 35.99 A C ATOM 485 CZ TYR A 60 73.661 72.128 13.739 1.00 36.24 A C ATOM 486 OH TYR A 60 73.406 71.510 14.936 1.00 40.70 A O ATOM 487 N ARG A 61 71.302 74.710 10.934 1.00 29.78 A N ATOM 488 CA ARG A 61 70.489 75.137 12.074 1.00 32.29 A C ATOM 489 C ARG A 61 70.289 73.992 13.056 1.00 35.05 A C ATOM 490 O ARG A 61 69.781 72.931 12.695 1.00 33.45 A O ATOM 491 CB ARG A 61 69.113 75.638 11.635 1.00 34.98 A C ATOM 492 CG ARG A 61 69.146 76.790 10.663 1.00 33.55 A C ATOM 493 CD ARG A 61 67.756 77.209 10.187 1.00 39.45 A C ATOM 494 NE ARG A 61 67.802 78.053 8.991 1.00 43.50 A N ATOM 495 CZ ARG A 61 66.737 78.400 8.267 1.00 43.32 A C ATOM 496 NH1 ARG A 61 65.517 77.969 8.591 1.00 43.64 A N ATOM 497 NH2 ARG A 61 66.896 79.173 7.201 1.00 43.55 A N ATOM 498 N ASP A 62 70.681 74.222 14.302 1.00 32.81 A N ATOM 499 CA ASP A 62 70.488 73.277 15.385 1.00 34.32 A C ATOM 500 C ASP A 62 69.019 73.222 15.812 1.00 35.83 A C ATOM 501 O ASP A 62 68.368 74.257 15.972 1.00 37.43 A O ATOM 502 CB ASP A 62 71.385 73.703 16.561 1.00 36.21 A C ATOM 503 CG ASP A 62 71.724 72.567 17.509 1.00 37.73 A C ATOM 504 OD1 ASP A 62 71.078 71.513 17.462 1.00 39.38 A O ATOM 505 OD2 ASP A 62 72.632 72.654 18.366 1.00 38.06 A O ATOM 506 N LEU A 63 68.504 72.009 16.000 1.00 32.04 A N ATOM 507 CA LEU A 63 67.151 71.799 16.496 1.00 33.21 A C ATOM 508 C LEU A 63 67.155 71.580 18.003 1.00 31.37 A C ATOM 509 O LEU A 63 66.108 71.522 18.621 1.00 33.62 A O ATOM 510 CB LEU A 63 66.489 70.603 15.793 1.00 32.30 A C ATOM 511 CG LEU A 63 65.919 70.957 14.417 1.00 37.47 A C ATOM 512 CD1 LEU A 63 65.566 69.688 13.604 1.00 37.52 A C ATOM 513 CD2 LEU A 63 64.696 71.880 14.549 1.00 37.36 A C ATOM 514 N ARG A 64 68.345 71.460 18.580 1.00 34.84 A N ATOM 515 CA ARG A 64 68.514 71.279 20.012 1.00 34.85 A C ATOM 516 C ARG A 64 67.687 70.109 20.516 1.00 37.89 A C ATOM 517 O ARG A 64 66.925 70.220 21.474 1.00 37.04 A O ATOM 518 CB ARG A 64 68.180 72.583 20.753 1.00 37.97 A C ATOM 519 CG ARG A 64 68.865 73.821 20.152 1.00 37.97 A C ATOM 520 CD ARG A 64 68.726 75.089 21.000 1.00 41.38 A C ATOM 521 NE ARG A 64 69.447 74.699 22.367 0.00 47.96 A N ATOM 522 CZ ARG A 64 69.722 75.629 23.275 0.00 49.03 A C ATOM 523 NH1 ARG A 64 69.491 76.907 23.009 0.00 49.64 A N ATOM 524 NH2 ARG A 64 70.226 75.281 24.451 0.00 49.89 A N ATOM 525 N LYS A 65 67.844 68.973 19.843 1.00 34.71 A N ATOM 526 CA LYS A 65 67.212 67.732 20.266 1.00 35.06 A C ATOM 527 C LYS A 65 68.076 66.577 19.771 1.00 30.42 A C ATOM 528 O LYS A 65 68.655 66.665 18.695 1.00 31.69 A O ATOM 529 CB LYS A 65 65.801 67.642 19.676 1.00 39.80 A C ATOM 530 CG LYS A 65 64.967 66.448 20.138 1.00 43.42 A C ATOM 531 CD LYS A 65 63.513 66.564 19.672 1.00 47.97 A C ATOM 532 CE LYS A 65 62.653 65.440 20.263 1.00 50.01 A C ATOM 533 NZ LYS A 65 61.233 65.463 19.797 1.00 51.34 A N ATOM 534 N GLY A 66 68.190 65.522 20.565 1.00 31.22 A N ATOM 535 CA GLY A 66 68.910 64.339 20.149 1.00 31.55 A C ATOM 536 C GLY A 66 67.996 63.249 19.616 1.00 32.06 A C ATOM 537 O GLY A 66 66.772 63.399 19.632 1.00 33.71 A O ATOM 538 N VAL A 67 68.617 62.153 19.163 1.00 30.61 A N ATOM 539 CA VAL A 67 67.927 60.946 18.675 1.00 32.04 A C ATOM 540 C VAL A 67 68.756 59.693 18.978 1.00 32.39 A C ATOM 541 O VAL A 67 69.982 59.724 18.870 1.00 29.49 A O ATOM 542 CB VAL A 67 67.663 61.024 17.158 1.00 34.97 A C ATOM 543 CG1 VAL A 67 66.568 61.988 16.878 1.00 40.45 A C ATOM 544 CG2 VAL A 67 68.912 61.440 16.387 1.00 36.19 A C ATOM 545 N TYR A 68 68.108 58.602 19.384 1.00 32.50 A N ATOM 546 CA TYR A 68 68.817 57.361 19.709 1.00 36.46 A C ATOM 547 C TYR A 68 68.113 56.190 19.062 1.00 34.88 A C ATOM 548 O TYR A 68 66.962 55.916 19.383 1.00 36.97 A O ATOM 549 CB TYR A 68 68.902 57.148 21.229 1.00 36.07 A C ATOM 550 CG TYR A 68 69.801 55.993 21.670 1.00 41.81 A C ATOM 551 CD1 TYR A 68 69.460 54.665 21.395 1.00 43.38 A C ATOM 552 CD2 TYR A 68 70.981 56.226 22.379 1.00 44.20 A C ATOM 553 CE1 TYR A 68 70.274 53.605 21.798 1.00 43.39 A C ATOM 554 CE2 TYR A 68 71.805 55.167 22.789 1.00 44.55 A C ATOM 555 CZ TYR A 68 71.444 53.863 22.492 1.00 45.41 A C ATOM 556 OH TYR A 68 72.242 52.807 22.897 1.00 47.48 A O ATOM 557 N VAL A 69 68.826 55.477 18.196 1.00 33.48 A N ATOM 558 CA VAL A 69 68.249 54.404 17.376 1.08 34.57 A C ATOM 559 C VAL A 69 68.922 53.080 17.716 1.00 34.34 A C ATOM 560 O VAL A 69 69.996 52.793 17.192 1.00 28.53 A O ATOM 561 CB VAL A 69 68.440 54.691 15.866 1.00 35.13 A C ATOM 562 CG1 VAL A 69 67.944 53.526 15.002 1.00 38.45 A C ATOM 563 CG2 VAL A 69 67.754 56.000 15.484 1.00 36.74 A C ATOM 564 N PRO A 70 68.319 52.269 18.588 1.00 39.88 A N ATOM 565 CA PRO A 70 68.846 50.922 18.830 1.00 43.50 A C ATOM 566 C PRO A 70 68.577 50.028 17.629 1.00 47.11 A C ATOM 567 O PRO A 70 67.551 50.175 16.960 1.00 41.77 A O ATOM 568 CB PRO A 70 68.097 50.428 20.077 1.00 44.42 A C ATOM 569 CG PRO A 70 67.031 51.423 20.368 1.00 43.58 A C ATOM 570 CD PRO A 70 67.125 52.554 19.397 1.00 42.11 A C ATOM 571 N TYR A 71 69.527 49.140 17.367 1.00 51.98 A N ATOM 572 CA TYR A 71 69.474 48.179 16.276 1.00 56.73 A C ATOM 573 C TYR A 71 69.683 46.796 16.908 1.00 58.39 A C ATOM 574 O TYR A 71 69.428 46.618 18.105 1.00 57.75 A O ATOM 575 CB TYR A 71 70.558 48.519 15.229 1.00 57.66 A C ATOM 576 CG TYR A 71 70.091 49.405 14.090 1.00 59.91 A C ATOM 577 CD1 TYR A 71 70.760 50.591 13.779 1.00 60.36 A C ATOM 578 CD2 TYR A 71 68.995 49.049 13.304 1.00 61.59 A C ATOM 579 CE1 TYR A 71 70.334 51.408 12.725 1.00 60.84 A C ATOM 580 CE2 TYR A 71 68.568 49.857 12.249 1.00 62.07 A C ATOM 581 CZ TYR A 71 69.241 51.035 11.966 1.00 63.27 A C ATOM 582 OH TYR A 71 68.818 51.840 10.924 1.00 64.04 A O ATOM 583 N THR A 72 70.147 45.832 16.114 1.00 61.01 A N ATOM 584 CA THR A 72 70.319 44.444 16.556 1.00 60.90 A C ATOM 585 C THR A 72 71.093 44.294 17.877 1.00 59.74 A C ATOM 586 O THR A 72 70.491 44.060 18.931 1.00 58.04 A O ATOM 587 CB THR A 72 70.993 43.609 15.431 1.00 62.06 A C ATOM 588 OG1 THR A 72 72.170 44.276 14.951 1.00 61.28 A O ATOM 589 CG2 THR A 72 70.090 43.514 14.196 1.00 63.15 A C ATOM 590 N GLN A 73 72.418 44.402 17.800 1.00 57.85 A N ATOM 591 CA GLN A 73 73.287 44.461 18.971 1.00 57.41 A C ATOM 592 C GLN A 73 74.155 45.726 18.850 1.00 54.83 A C ATOM 593 O GLN A 73 75.303 45.747 19.299 1.00 57.07 A O ATOM 594 CB GLN A 73 74.153 43.194 19.060 1.00 58.83 A C ATOM 595 CG GLN A 73 73.865 42.294 20.273 1.00 60.65 A C ATOM 596 CD GLN A 73 74.720 42.630 21.504 1.00 63.27 A C ATOM 597 OE1 GLN A 73 75.959 42.582 21.450 1.00 61.11 A O ATOM 598 NE2 GLN A 73 74.058 42.943 22.619 1.00 61.34 A N ATOM 599 N GLY A 74 73.591 46.763 18.223 1.00 48.16 A N ATOM 600 CA GLY A 74 74.262 48.041 18.020 1.00 42.89 A C ATOM 601 C GLY A 74 73.290 49.214 18.016 1.00 38.35 A C ATOM 602 O GLY A 74 72.224 49.115 18.625 1.00 39.09 A O ATOM 603 N LYS A 75 73.656 50.320 17.360 1.00 32.71 A N ATOM 604 CA LYS A 75 72.844 51.554 17.362 1.00 31.39 A C ATOM 605 C LYS A 75 73.525 52.762 16.664 1.00 24.85 A C ATOM 606 O LYS A 75 74.685 52.698 16.338 1.00 21.55 A O ATOM 607 CB LYS A 75 72.483 51.946 18.800 1.00 34.61 A C ATOM 608 CG LYS A 75 73.667 52.144 19.731 1.00 39.32 A C ATOM 609 CD LYS A 75 74.545 53.318 19.299 1.00 39.96 A C ATOM 610 CE LYS A 75 75.034 54.144 20.451 1.00 40.91 A C ATOM 611 NZ LYS A 75 74.297 55.407 20.464 1.00 45.34 A N ATOM 612 N TRP A 76 72.782 53.843 16.434 1.00 22.44 A N ATOM 613 CA TRP A 76 73.372 55.173 16.224 1.00 25.02 A C ATOM 614 C TRP A 76 72.594 56.201 17.012 1.00 23.16 A C ATOM 615 O TRP A 76 71.429 56.007 17.353 1.00 21.34 A O ATOM 616 CB TRP A 76 73.512 55.570 14.732 1.00 24.36 A C ATOM 617 CG TRP A 76 72.243 55.752 13.957 1.00 25.79 A C ATOM 618 CD1 TRP A 76 71.643 54.833 13.136 1.00 26.34 A C ATOM 619 CD2 TRP A 76 71.424 56.932 13.896 1.00 21.29 A C ATOM 620 NE1 TRP A 76 70.491 55.364 12.595 1.00 27.23 A N ATOM 621 CE2 TRP A 76 70.348 56.656 13.030 1.00 25.91 A C ATOM 622 CE3 TRP A 76 71.497 58.202 14.479 1.00 24.01 A C ATOM 623 CZ2 TRP A 76 69.349 57.595 12.752 1.00 26.87 A C ATOM 624 CZ3 TRP A 76 70.512 59.124 14.202 1.00 26.34 A C ATOM 625 CH2 TRP A 76 69.448 58.818 13.345 1.00 25.94 A C ATOM 626 N GLU A 77 73.291 57.271 17.354 1.00 22.20 A N ATOM 627 CA GLU A 77 72.753 58.327 18.164 1.00 24.84 A C ATOM 628 C GLU A 77 73.255 59.632 17.575 1.00 22.78 A C ATOM 629 O GLU A 77 74.386 59.723 17.089 1.00 19.61 A O ATOM 630 CB GLU A 77 73.214 58.140 19.621 1.00 28.88 A C ATOM 631 CG GLU A 77 72.959 59.331 20.529 1.00 35.35 A C ATOM 632 CD GLU A 77 73.323 59.057 21.980 0.50 36.38 A C ATOM 633 OE1 GLU A 77 74.397 58.470 22.222 0.50 42.18 A O ATOM 634 OE2 GLU A 77 72.536 59.431 22.878 0.50 39.02 A O ATOM 635 N GLY A 78 72.418 60.651 17.573 1.00 24.09 A N ATOM 636 CA GLY A 78 72.811 61.883 16.933 1.00 25.68 A C ATOM 637 C GLY A 78 72.160 63.134 17.453 1.00 25.43 A C ATOM 638 O GLY A 78 71.328 63.116 18.350 1.00 27.93 A O ATOM 639 N GLU A 79 72.579 64.234 16.861 1.00 23.79 A N ATOM 640 CA GLU A 79 72.078 65.542 17.187 1.00 23.88 A C ATOM 641 C GLU A 79 71.283 65.981 15.979 1.00 22.32 A C ATOM 642 O GLU A 79 71.800 65.979 14.875 1.00 26.62 A O ATOM 643 CB GLU A 79 73.255 66.487 17.457 1.00 23.99 A C ATOM 644 CG GLU A 79 74.109 66.052 18.641 1.00 29.60 A C ATOM 645 CD GLU A 79 75.420 66.826 18.790 1.00 33.85 A C ATOM 646 OE1 GLU A 79 76.205 66.467 19.685 1.00 34.63 A O ATOM 647 OE2 GLU A 79 75.670 67.782 18.030 1.00 37.21 A O ATOM 648 N LEU A 80 70.017 66.338 16.180 1.00 22.69 A N ATOM 649 CA LEU A 80 69.184 66.809 15.075 1.00 24.78 A C ATOM 650 C LEU A 80 69.419 68.267 14.685 1.00 26.56 A C ATOM 651 O LEU A 80 69.596 69.139 15.528 1.00 26.06 A O ATOM 652 CB LEU A 80 67.704 66.617 15.403 1.00 26.07 A C ATOM 653 CG LEU A 80 67.233 65.168 15.432 1.00 31.35 A C ATOM 654 CD1 LEU A 80 65.863 65.082 16.077 1.00 28.71 A C ATOM 655 CD2 LEU A 80 67.212 64.609 14.015 1.00 32.32 A C ATOM 656 N GLY A 81 69.390 68.525 13.383 1.00 23.46 A N ATOM 657 CA GLY A 81 69.500 69.861 12.822 1.00 22.46 A C ATOM 658 C GLY A 81 68.854 69.916 11.448 1.00 26.63 A C ATOM 659 O GLY A 81 68.308 68.927 11.002 1.00 22.44 A O ATOM 660 N THR A 82 68.884 71.065 10.787 1.00 26.31 A N ATOM 661 CA THR A 82 68.530 71.138 9.369 1.00 28.52 A C ATOM 662 C THR A 82 69.634 71.813 8.631 1.00 25.22 A C ATOM 663 O THR A 82 70.436 72.529 9.225 1.00 27.82 A O ATOM 664 CB THR A 82 67.190 71.888 9.127 1.00 29.47 A C ATOM 665 OG1 THR A 82 67.310 73.253 9.554 1.00 27.90 A O ATOM 666 CG2 THR A 62 66.069 71.306 9.972 1.00 30.70 A C ATOM 667 N ASP A 83 69.704 71.567 7.326 1.00 24.75 A N ATOM 668 CA ASP A 83 70.679 72.180 6.447 1.00 22.11 A C ATOM 669 C ASP A 83 70.241 71.993 5.009 1.00 24.09 A C ATOM 670 O ASP A 83 69.261 71.285 4.741 1.00 26.17 A O ATOM 671 CB ASP A 83 72.075 71.559 6.652 1.00 24.10 A C ATOM 672 CG ASP A 83 73.213 72.542 6.376 1.00 26.19 A C ATOM 673 OD1 ASP A 83 73.067 73.513 5.580 1.00 27.95 A O ATOM 674 OD2 ASP A 83 74.328 72.409 6.924 1.00 25.64 A O ATOM 675 N LEU A 84 70.973 72.591 4.081 1.00 26.89 A N ATOM 676 CA LEU A 84 70.641 72.502 2.658 1.00 27.35 A C ATOM 677 C LEU A 84 71.224 71.225 2.078 1.00 28.51 A C ATOM 678 O LEU A 84 72.398 70.936 2.266 1.00 25.25 A O ATOM 679 CB LEU A 84 71.193 73.717 1.915 1.00 29.63 A C ATOM 680 CG LEU A 84 70.550 75.047 2.345 1.00 31.38 A C ATOM 681 CD1 LEU A 84 71.025 76.228 1.501 1.00 30.45 A C ATOM 682 CD2 LEU A 84 69.027 74.949 2.301 1.00 30.98 A C ATOM 683 N VAL A 85 70.392 70.465 1.373 1.00 25.49 A N ATOM 684 CA VAL A 85 70.790 69.203 0.768 1.00 28.08 A C ATOM 685 C VAL A 85 70.523 69.177 −0.737 1.00 27.65 A C ATOM 686 O VAL A 85 69.511 69.686 −1.213 1.00 27.43 A O ATOM 687 CB VAL A 85 70.063 68.028 1.439 1.00 27.18 A C ATOM 688 CG1 VAL A 85 70.564 66.696 0.875 1.00 27.97 A C ATOM 689 CG2 VAL A 85 70.273 68.084 2.950 1.00 29.93 A C ATOM 690 N SER A 86 71.451 68.587 −1.472 1.00 28.67 A N ATOM 691 CA SER A 86 71.331 68.409 −2.913 1.00 30.97 A C ATOM 692 C SER A 86 71.823 67.015 −3.293 1.00 31.51 A C ATOM 693 O SER A 86 72.512 66.354 −2.509 1.00 25.69 A O ATOM 694 CB SER A 86 72.138 69.485 −3.642 1.00 33.70 A C ATOM 695 OG SER A 86 71.607 69.737 −4.930 1.00 42.01 A O ATOM 696 N ILE A 87 71.459 66.563 −4.494 1.00 24.97 A N ATOM 697 CA ILE A 87 71.895 65.277 −5.006 1.00 25.75 A C ATOM 698 C ILE A 87 72.489 65.559 −6.384 1.00 29.06 A C ATOM 699 O ILE A 87 71.737 65.734 −7.354 1.00 27.25 A O ATOM 700 CB ILE A 87 70.713 64.275 −5.094 1.00 25.77 A C ATOM 701 CG1 ILE A 87 70.062 64.090 −3.729 1.00 26.43 A C ATOM 702 CG2 ILE A 87 71.187 62.939 −5.631 1.00 23.43 A C ATOM 703 CD1 ILE A 87 68.758 63.332 −3.747 1.00 29.21 A C ATOM 704 N PRO A 88 73.817 65.654 −6.453 1.00 29.18 A N ATOM 705 CA PRO A 88 74.531 66.013 −7.689 1.00 30.76 A C ATOM 706 C PRO A 88 74.063 65.286 −8.956 1.00 32.20 A C ATOM 707 O PRO A 88 73.924 65.938 −9.987 1.00 33.45 A O ATOM 708 CB PRO A 88 75.971 65.632 −7.358 1.00 31.55 A C ATOM 709 CG PRO A 88 76.067 65.895 −5.896 1.00 30.46 A C ATOM 710 CD PRO A 88 74.762 65.455 −5.339 1.00 28.40 A C ATOM 711 N HIS A 89 73.857 63.972 −8.872 1.00 27.36 A N ATOM 712 CA HIS A 89 73.332 63.162 −9.978 1.00 28.26 A C ATOM 713 C HIS A 89 71.871 62.815 −9.715 1.00 29.29 A C ATOM 714 O HIS A 89 71.449 61.661 −9.847 1.00 28.09 A O ATOM 715 CB HIS A 89 74.173 61.907 −10.160 1.00 28.17 A C ATOM 716 CG HIS A 89 75.632 62.184 −10.362 1.00 38.05 A C ATOM 717 ND1 HIS A 89 76.120 62.833 −11.478 1.00 41.06 A N ATOM 718 CD2 HIS A 89 76.708 61.905 −9.588 1.00 38.74 A C ATOM 719 CE1 HIS A 89 77.435 62.933 −11.384 1.00 40.63 A C ATOM 720 NE2 HIS A 89 77.817 62.376 −10.248 1.00 41.19 A N ATOM 721 N GLY A 90 71.120 63.846 −9.334 1.00 32.50 A N ATOM 722 CA GLY A 90 69.696 63.769 −9.051 1.00 31.86 A C ATOM 723 C GLY A 90 69.005 64.963 −9.686 1.00 30.26 A C ATOM 724 O GLY A 90 69.524 65.524 −10.644 1.00 31.12 A O ATOM 725 N PRO A 91 67.861 65.382 −9.158 1.00 32.37 A N ATOM 726 CA PRO A 91 67.175 66.565 −9.691 1.00 34.88 A C ATOM 727 C PRO A 91 67.987 67.835 −9.410 1.00 39.91 A C ATOM 728 O PRO A 91 68.764 67.852 −8.458 1.00 38.58 A O ATOM 729 CB PRO A 91 65.837 66.579 −8.937 1.00 35.23 A C ATOM 730 CG PRO A 91 66.049 65.738 −7.711 1.00 34.49 A C ATOM 731 CD PRO A 91 67.164 64.807 −7.994 1.00 33.82 A C ATOM 732 N ASN A 92 67.809 68.863 −10.238 1.00 43.06 A N ATOM 733 CA ASN A 92 68.496 70.152 −10.086 1.00 45.05 A C ATOM 734 C ASN A 92 67.841 71.060 −9.034 1.00 44.59 A C ATOM 735 O ASN A 92 67.368 72.156 −9.337 1.00 44.08 A O ATOM 736 CB ASN A 92 68.546 70.860 −11.441 1.00 47.21 A C ATOM 737 CG ASN A 92 69.438 72.079 −11.431 1.00 50.71 A C ATOM 738 OD1 ASN A 92 70.604 72.003 −11.044 1.00 52.68 A O ATOM 739 ND2 ASN A 92 68.895 73.217 −11.863 1.00 52.24 A N ATOM 740 N VAL A 93 67.830 70.592 −7.789 1.00 41.78 A N ATOM 741 CA VAL A 93 67.205 71.310 −6.691 1.00 36.70 A C ATOM 742 C VAL A 93 68.043 71.217 −5.428 1.00 35.54 A C ATOM 743 O VAL A 93 68.907 70.353 −5.304 1.00 36.77 A O ATOM 744 CB VAL A 93 65.794 70.772 −6.374 1.00 38.91 A C ATOM 745 CG1 VAL A 93 64.868 70.960 −7.573 1.00 37.74 A C ATOM 746 CG2 VAL A 93 65.848 69.310 −5.921 1.00 37.34 A C ATOM 747 N THR A 94 67.772 72.139 −4.513 1.00 33.85 A N ATOM 748 CA THR A 94 68.320 72.119 −3.178 1.00 35.85 A C ATOM 749 C THR A 94 67.170 72.293 −2.216 1.00 36.41 A C ATOM 750 O THR A 94 66.283 73.119 −2.443 1.00 38.29 A O ATOM 751 CB THR A 94 69.327 73.252 −3.009 1.00 37.46 A C ATOM 752 OG1 THR A 94 70.459 73.016 −3.855 1.00 37.95 A O ATOM 753 CG2 THR A 94 69.910 73.256 −1.599 1.00 39.22 A C ATOM 754 N VAL A 95 67.162 71.515 −1.143 1.00 32.79 A N ATOM 755 CA VAL A 95 66.110 71.652 −0.155 1.00 32.68 A C ATOM 756 C VAL A 95 66.660 71.686 1.261 1.00 30.49 A C ATOM 757 O VAL A 95 67.762 71.240 1.499 1.00 31.56 A O ATOM 758 CB VAL A 95 65.071 70.544 −0.291 1.00 36.55 A C ATOM 759 CG1 VAL A 95 64.479 70.568 −1.709 1.00 38.67 A C ATOM 760 CG2 VAL A 95 65.663 69.183 0.025 1.00 33.09 A C ATOM 761 N ARG A 96 65.883 72.244 2.181 1.00 30.99 A N ATOM 762 CA ARG A 96 66.212 72.215 3.597 1.00 29.56 A C ATOM 763 C ARG A 96 65.620 70.957 4.208 1.00 28.73 A C ATOM 764 O ARG A 96 64.402 70.809 4.302 1.00 30.19 A O ATOM 765 CB ARG A 96 65.686 73.459 4.320 1.00 33.02 A C ATOM 766 CG ARG A 96 65.976 73.474 5.835 1.00 36.80 A C ATOM 767 CD ARG A 96 65.954 74.863 6.457 1.00 38.14 A C ATOM 768 NE ARG A 96 67.041 75.677 5.929 1.00 37.92 A N ATOM 769 CZ ARG A 96 68.265 75.747 6.442 1.00 37.97 A C ATOM 770 NH1 ARG A 96 68.600 75.050 7.524 1.00 38.44 A N ATOM 771 NH2 ARG A 96 69.160 76.512 5.846 1.00 33.62 A N ATOM 772 N ALA A 97 66.503 70.048 4.606 1.00 24.74 A N ATOM 773 CA ALA A 97 66.126 68.764 5.167 1.00 27.21 A C ATOM 774 C ALA A 97 66.541 68.668 6.614 1.00 22.38 A C ATOM 775 O ALA A 97 67.523 69.278 7.026 1.00 23.68 A O ATOM 776 CB ALA A 97 66.801 67.648 4.380 1.00 24.80 A C ATOM 777 N ASN A 98 65.796 67.884 7.378 1.00 21.67 A N ATOM 778 CA ASN A 98 66.281 67.388 8.644 1.00 22.81 A C ATOM 779 C ASN A 98 67.502 66.503 8.409 1.00 25.29 A C ATOM 780 O ASN A 98 67.538 65.738 7.451 1.00 21.43 A O ATOM 781 CB ASN A 98 65.184 66.605 9.351 1.00 23.87 A C ATOM 782 CG ASN A 98 64.033 67.503 9.805 1.00 31.55 A C ATOM 783 OD1 ASN A 98 64.257 68.532 10.448 1.00 28.77 A O ATOM 784 ND2 ASN A 98 62.801 67.115 9.469 1.00 29.01 A N ATOM 785 N ILE A 99 68.517 66.652 9.255 1.00 23.47 A N ATOM 786 CA ILE A 99 69.693 65.781 9.240 1.00 21.95 A C ATOM 787 C ILE A 99 70.048 65.437 10.685 1.00 19.63 A C ATOM 788 O ILE A 99 70.186 66.339 11.529 1.00 24.71 A O ATOM 789 CB ILE A 99 70.902 66.475 8.586 1.00 22.78 A C ATOM 790 CG1 ILE A 99 70.571 66.968 7.184 1.00 19.57 A C ATOM 791 CG2 ILE A 99 72.076 65.544 8.527 1.00 25.77 A C ATOM 792 CD1 ILE A 99 71.663 67.806 6.568 1.00 26.04 A C ATOM 793 N ALA A 100 70.167 64.149 10.968 1.00 17.47 A N ATOM 794 CA ALA A 100 70.721 63.657 12.223 1.00 17.42 A C ATOM 795 C ALA A 100 72.245 63.532 12.075 1.00 21.54 A C ATOM 796 O ALA A 100 72.742 62.697 11.325 1.00 18.72 A O ATOM 797 CB ALA A 100 70.116 62.345 12.607 1.00 21.16 A C ATOM 798 N ALA A 101 72.981 64.369 12.804 1.00 18.65 A N ATOM 799 CA ALA A 101 74.436 64.308 12.819 1.00 19.52 A C ATOM 800 C ALA A 101 74.849 63.244 13.813 1.00 19.24 A C ATOM 801 O ALA A 101 74.595 63.358 15.017 1.00 22.30 A O ATOM 802 CB ALA A 101 75.052 65.702 13.163 1.00 21.40 A C ATOM 803 N ILE A 102 75.398 62.150 13.311 1.00 15.90 A N ATOM 804 CA ILE A 102 75.660 60.973 14.129 1.00 17.94 A C ATOM 805 C ILE A 102 76.952 61.245 14.892 1.00 19.52 A C ATOM 806 O ILE A 102 77.978 61.511 14.288 1.00 19.99 A O ATOM 807 CB ILE A 102 75.842 59.690 13.277 1.00 15.21 A C ATOM 808 CG1 ILE A 102 74.554 59.374 12.505 1.00 16.99 A C ATOM 809 CG2 ILE A 102 76.224 58.519 14.178 1.00 18.39 A C ATOM 810 CD1 ILE A 102 74.673 58.276 11.472 1.00 19.74 A C ATOM 811 N THR A 103 76.866 61.146 16.212 1.00 21.46 A N ATOM 812 CA THR A 103 77.982 61.450 17.114 1.00 25.21 A C ATOM 813 C THR A 103 78.451 60.245 17.925 1.00 26.42 A C ATOM 814 O THR A 103 79.504 60.296 18.556 1.00 27.83 A O ATOM 815 CB THR A 103 77.556 62.579 18.073 1.00 24.52 A C ATOM 816 OG1 THR A 103 76.344 62.216 18.746 1.00 26.84 A O ATOM 817 CG2 THR A 103 77.183 63.831 17.317 1.00 25.79 A C ATOM 818 N GLU A 104 77.668 59.168 17.934 1.00 23.45 A N ATOM 819 CA GLU A 104 78.061 57.917 18.576 1.00 19.81 A C ATOM 820 C GLU A 104 77.351 56.767 17.877 1.00 21.65 A C ATOM 821 O GLU A 104 76.208 56.921 17.465 1.00 21.87 A O ATOM 822 CB GLU A 104 77.725 57.928 20.088 1.00 28.17 A C ATOM 823 CG GLU A 104 78.291 56.737 20.854 1.00 33.07 A C ATOM 824 CD GLU A 104 77.964 56.726 22.350 1.00 42.35 A C ATOM 825 OE1 GLU A 104 77.594 57.785 22.928 1.00 48.99 A O ATOM 826 OE2 GLU A 104 78.089 55.637 22.961 1.00 51.21 A O ATOM 827 N SER A 105 78.043 55.649 17.693 1.00 19.13 A N ATOM 828 CA SER A 105 77.446 54.481 17.026 1.00 20.88 A C ATOM 829 C SER A 105 78.126 53.167 17.421 1.00 24.82 A C ATOM 830 O SER A 105 79.260 53.151 17.929 1.00 23.75 A O ATOM 831 CB SER A 105 77.440 54.676 15.490 1.00 18.17 A C ATOM 832 OG SER A 105 78.758 54.663 15.012 1.00 21.83 A O ATOM 833 N ASP A 106 77.400 52.072 17.214 1.00 22.55 A N ATOM 834 CA ASP A 106 77.913 50.733 17.411 1.00 24.69 A C ATOM 835 C ASP A 106 77.315 49.839 16.312 1.00 23.68 A C ATOM 836 O ASP A 106 76.094 49.837 16.093 1.00 22.98 A O ATOM 837 CB ASP A 106 77.556 50.196 18.792 1.00 29.23 A C ATOM 838 CG ASP A 106 77.998 48.751 18.973 0.50 30.82 A C ATOM 839 OD1 ASP A 106 79.136 48.520 19.419 0.50 35.18 A O ATOM 840 OD2 ASP A 106 77.279 47.781 18.668 0.50 34.57 A O ATOM 841 N LYS A 107 78.190 49.123 15.618 1.00 25.54 A N ATOM 842 CA LYS A 107 77.820 48.161 14.572 1.00 22.36 A C ATOM 843 C LYS A 107 76.966 48.753 13.446 1.00 25.69 A C ATOM 844 O LYS A 107 76.176 48.054 12.825 1.00 22.57 A O ATOM 845 CB LYS A 107 77.139 46.935 15.195 1.00 27.43 A C ATOM 846 CG LYS A 107 78.066 46.130 16.101 1.00 32.24 A C ATOM 847 CD LYS A 107 77.314 45.034 16.835 1.00 33.50 A C ATOM 848 CE LYS A 107 78.004 44.328 17.899 0.00 31.63 A C ATOM 849 NZ LYS A 107 79.348 43.882 17.435 0.00 31.79 A N ATOM 850 N PHE A 108 77.151 50.043 13.187 1.00 22.67 A N ATOM 851 CA PHE A 108 76.412 50.770 12.161 1.00 20.97 A C ATOM 852 C PHE A 108 77.306 50.946 10.954 1.00 19.92 A C ATOM 853 O PHE A 108 77.016 50.416 9.875 1.00 21.69 A O ATOM 854 CB PHE A 108 75.946 52.125 12.691 1.00 19.57 A C ATOM 855 CG PHE A 108 75.153 52.921 11.701 1.00 20.66 A C ATOM 856 CD1 PHE A 108 73.870 52.520 11.338 1.00 25.16 A C ATOM 857 CD2 PHE A 108 75.688 54.053 11.107 1.00 22.61 A C ATOM 858 CE1 PHE A 108 73.139 53.250 10.405 1.00 25.50 A C ATOM 859 CE2 PHE A 108 74.963 54.790 10.190 1.00 22.84 A C ATOM 860 CZ PHE A 108 73.677 54.381 9.832 1.00 26.62 A C ATOM 861 N PHE A 109 78.401 51.682 11.129 1.00 20.35 A N ATOM 862 CA PHE A 109 79.372 51.887 10.044 1.00 20.96 A C ATOM 863 C PHE A 109 80.123 50.581 9.813 1.00 19.74 A C ATOM 864 O PHE A 109 80.361 49.824 10.769 1.00 24.70 A O ATOM 865 CB PHE A 109 80.325 53.065 10.348 1.00 19.85 A C ATOM 866 CG PHE A 109 79.617 54.398 10.489 1.00 16.19 A C ATOM 867 CD1 PHE A 109 78.862 54.897 9.435 1.00 22.18 A C ATOM 868 CD2 PHE A 109 79.726 55.162 11.633 1.00 22.85 A C ATOM 869 CE1 PHE A 109 78.197 56.107 9.532 1.00 21.10 A C ATOM 870 CE2 PHE A 109 79.066 56.377 11.728 1.00 21.43 A C ATOM 871 CZ PHE A 109 78.284 56.841 10.663 1.00 22.40 A C ATOM 872 N ILE A 110 80.460 50.285 8.556 1.00 24.38 A N ATOM 873 CA ILE A 110 81.176 49.060 8.204 1.00 23.73 A C ATOM 874 C ILE A 110 82.627 49.382 7.863 1.00 25.17 A C ATOM 875 O ILE A 110 82.917 50.295 7.077 1.00 21.65 A O ATOM 876 CB ILE A 110 80.510 48.364 6.998 1.00 23.43 A C ATOM 877 CG1 ILE A 110 79.073 47.944 7.330 1.00 26.13 A C ATOM 878 CG2 ILE A 110 81.354 47.171 6.511 1.00 27.63 A C ATOM 879 CD1 ILE A 110 78.262 47.542 6.104 1.00 29.01 A C ATOM 880 N ASN A 111 83.535 48.616 8.453 1.00 24.01 A N ATOM 881 CA ASN A 111 84.958 48.786 8.213 1.00 25.66 A C ATOM 882 C ASN A 111 85.302 48.367 6.782 1.00 21.62 A C ATOM 883 O ASN A 111 85.122 47.210 6.395 1.00 24.50 A O ATOM 884 CB ASN A 111 85.762 47.950 9.219 1.00 26.77 A C ATOM 885 CG ASN A 111 87.239 48.324 9.252 1.00 30.39 A C ATOM 886 OD1 ASN A 111 87.614 49.478 9.012 1.00 29.76 A O ATOM 887 ND2 ASN A 111 88.081 47.348 9.588 1.00 28.98 A N ATOM 888 N GLY A 112 85.815 49.310 6.008 1.00 21.53 A N ATOM 889 CA GLY A 112 86.127 49.082 4.604 1.00 26.83 A C ATOM 890 C GLY A 112 85.073 49.602 3.630 1.00 27.54 A C ATOM 891 O GLY A 112 85.274 49.562 2.419 1.00 26.87 A O ATOM 892 N SER A 113 83.950 50.086 4.145 1.00 28.16 A N ATOM 893 CA SER A 113 82.869 50.607 3.301 1.00 23.29 A C ATOM 894 C SER A 113 83.152 52.034 2.864 1.00 22.88 A C ATOM 895 O SER A 113 83.981 52.730 3.462 1.00 22.23 A O ATOM 896 CB SER A 113 81.537 50.544 4.053 1.00 26.77 A C ATOM 897 OG SER A 113 81.450 51.622 4.968 1.00 32.46 A O ATOM 898 N ASN A 114 82.451 52.469 1.818 1.00 19.83 A N ATOM 899 CA ASN A 114 82.632 53.785 1.195 1.00 20.70 A C ATOM 900 C ASN A 114 81.400 54.686 1.349 1.00 17.94 A C ATOM 901 O ASN A 114 81.228 55.627 0.596 1.00 20.08 A O ATOM 902 CB ASN A 114 82.973 53.574 −0.303 1.00 20.54 A C ATOM 903 CG ASN A 114 83.533 54.827 −1.004 1.00 26.09 A C ATOM 904 OD1 ASN A 114 83.189 55.100 −2.165 1.00 29.37 A O ATOM 905 ND2 ASN A 114 84.441 55.540 −0.348 1.00 22.18 A N ATOM 906 N TRP A 115 80.558 54.414 2.354 1.00 16.89 A N ATOM 907 CA TRP A 115 79.453 55.295 2.658 1.00 16.46 A C ATOM 908 C TRP A 115 79.548 55.772 4.100 1.00 18.12 A C ATOM 909 O TRP A 115 80.184 55.126 4.943 1.00 20.65 A O ATOM 910 CB TRP A 115 78.093 54.631 2.393 1.00 18.60 A C ATOM 911 CG TRP A 115 77.869 53.335 3.061 1.00 18.81 A C ATOM 912 CD1 TRP A 115 78.058 52.098 2.520 1.00 27.02 A C ATOM 913 CD2 TRP A 115 77.372 53.109 4.403 1.00 19.85 A C ATOM 914 NE1 TRP A 115 77.734 51.123 3.434 1.00 28.07 A N ATOM 915 CE2 TRP A 115 77.311 51.716 4.597 1.00 28.04 A C ATOM 916 CE3 TRP A 115 76.983 53.943 5.453 1.00 21.36 A C ATOM 917 CZ2 TRP A 115 76.877 51.142 5.799 1.00 27.30 A C ATOM 918 CZ3 TRP A 115 76.544 53.371 6.643 1.00 22.49 A C ATOM 919 CH2 TRP A 115 76.510 51.996 6.808 1.00 24.66 A C ATOM 920 N GLU A 116 78.910 56.905 4.345 1.00 18.09 A N ATOM 921 CA GLU A 116 79.049 57.666 5.584 1.00 18.37 A C ATOM 922 C GLU A 116 77.726 58.110 6.220 1.00 21.39 A C ATOM 923 O GLU A 116 77.719 58.866 7.185 1.00 19.69 A O ATOM 924 CB GLU A 116 79.891 58.924 5.282 1.00 21.09 A C ATOM 925 CG GLU A 116 81.298 58.664 4.834 1.00 30.57 A C ATOM 926 CD GLU A 116 81.495 58.683 3.331 1.00 19.12 A C ATOM 927 OE1 GLU A 116 80.945 59.571 2.609 1.00 25.47 A O ATOM 928 OE2 GLU A 116 82.237 57.811 2.889 1.00 30.78 A O ATOM 929 N GLY A 117 76.601 57.670 5.680 1.00 15.48 A N ATOM 930 CA GLY A 117 75.302 58.008 6.218 1.00 14.95 A C ATOM 931 C GLY A 117 74.221 57.194 5.523 1.00 17.22 A C ATOM 932 O GLY A 117 74.517 56.329 4.686 1.00 15.79 A O ATOM 933 N ILE A 118 72.980 57.475 5.888 1.00 18.20 A N ATOM 934 CA ILE A 118 71.810 56.721 5.455 1.00 12.85 A C ATOM 935 C ILE A 118 70.668 57.692 5.108 1.00 15.45 A C ATOM 936 O ILE A 118 70.426 58.691 5.805 1.00 15.49 A O ATOM 937 CB ILE A 118 71.401 55.687 6.518 1.00 16.49 A C ATOM 938 CG1 ILE A 118 70.260 54.788 6.018 1.00 20.60 A C ATOM 939 CG2 ILE A 118 70.977 56.368 7.820 1.00 18.54 A C ATOM 940 CD1 ILE A 118 69.959 53.672 6.975 1.00 22.49 A C ATOM 941 N LEU A 119 69.973 57.386 4.012 1.00 16.51 A N ATOM 942 CA LEU A 119 68.850 58.180 3.520 1.00 17.34 A C ATOM 943 C LEU A 119 67.605 57.332 3.631 1.00 17.57 A C ATOM 944 O LEU A 119 67.370 56.426 2.823 1.00 17.07 A O ATOM 945 CB LEU A 119 69.061 58.614 2.073 1.00 16.12 A C ATOM 946 CG LEU A 119 67.954 59.469 1.461 1.00 20.50 A C ATOM 947 CD1 LEU A 119 67.744 60.734 2.237 1.00 21.51 A C ATOM 948 CD2 LEU A 119 68.286 59.797 0.034 1.00 22.00 A C ATOM 949 N GLY A 120 66.817 57.600 4.659 1.00 15.26 A N ATOM 950 CA GLY A 120 65.590 56.864 4.892 1.00 16.17 A C ATOM 951 C GLY A 120 64.506 57.419 3.975 1.00 16.03 A C ATOM 952 O GLY A 120 64.131 58.593 4.102 1.00 20.14 A O ATOM 953 N LEU A 121 64.011 56.582 3.064 1.00 15.98 A N ATOM 954 CA LEU A 121 63.037 57.010 2.038 1.00 16.93 A C ATOM 955 C LEU A 121 61.586 56.616 2.330 1.00 18.71 A C ATOM 956 O LEU A 121 60.683 56.874 1.530 1.00 20.26 A O ATOM 957 CB LEU A 121 63.460 56.449 0.682 1.00 16.32 A C ATOM 958 CG LEU A 121 64.699 57.128 0.084 1.00 18.18 A C ATOM 959 CD1 LEU A 121 65.208 56.418 −1.167 1.00 17.74 A C ATOM 960 CD2 LEU A 121 64.505 58.626 −0.230 1.00 19.83 A C ATOM 961 N ALA A 122 61.377 55.931 3.440 1.00 17.96 A N ATOM 962 CA ALA A 122 60.037 55.568 3.916 1.00 19.62 A C ATOM 963 C ALA A 122 59.307 56.740 4.589 1.00 24.01 A C ATOM 964 O ALA A 122 59.734 57.890 4.476 1.00 24.71 A O ATOM 965 CB ALA A 122 60.130 54.361 4.829 1.00 20.17 A C ATOM 966 N TYR A 123 58.185 56.447 5.256 1.00 23.30 A N ATOM 967 CA TYR A 123 57.265 57.473 5.703 1.00 25.93 A C ATOM 968 C TYR A 123 57.492 57.894 7.163 1.00 23.41 A C ATOM 969 O TYR A 123 58.146 57.192 7.931 1.00 25.28 A O ATOM 970 CB TYR A 123 55.836 56.968 5.559 1.00 25.54 A C ATOM 971 CG TYR A 123 55.441 56.697 4.129 1.00 24.32 A C ATOM 972 CD1 TYR A 123 55.015 57.724 3.310 1.00 25.79 A C ATOM 973 CD2 TYR A 123 55.491 55.421 3.609 1.00 26.50 A C ATOM 974 CE1 TYR A 123 54.622 57.486 1.998 1.00 28.42 A C ATOM 975 CE2 TYR A 123 55.120 55.171 2.293 1.00 27.28 A C ATOM 976 CZ TYR A 123 54.678 56.195 1.501 1.00 25.25 A C ATOM 977 OH TYR A 123 54.315 55.950 0.184 1.00 26.89 A O ATOM 978 N ALA A 124 56.879 59.014 7.519 1.00 29.24 A N ATOM 979 CA ALA A 124 57.082 59.664 8.820 1.00 30.24 A C ATOM 980 C ALA A 124 56.708 58.812 10.018 1.00 35.27 A C ATOM 981 O ALA A 124 57.302 58.953 11.091 1.00 33.99 A O ATOM 982 CB ALA A 124 56.356 60.972 8.858 1.00 31.62 A C ATOM 983 N GLU A 125 55.754 57.903 9.834 1.00 34.28 A N ATOM 984 CA GLU A 125 55.295 57.003 10.894 1.00 37.92 A C ATOM 985 C GLU A 125 56.415 56.274 11.647 1.00 37.65 A C ATOM 986 O GLU A 125 56.299 56.030 12.853 1.00 38.82 A O ATOM 987 CB GLU A 125 54.330 55.968 10.293 1.00 40.24 A C ATOM 988 CG GLU A 125 53.444 55.252 11.295 1.00 45.50 A C ATOM 989 CD GLU A 125 52.121 55.962 11.496 1.00 52.07 A C ATOM 990 OE1 GLU A 125 52.131 57.123 11.977 1.00 54.94 A O ATOM 991 OE2 GLU A 125 51.075 55.364 11.163 1.00 57.37 A O ATOM 992 N ILE A 126 57.491 55.918 10.941 1.00 31.63 A N ATOM 993 CA ILE A 126 58.585 55.155 11.525 1.00 28.26 A C ATOM 994 C ILE A 126 59.866 55.991 11.687 1.00 26.21 A C ATOM 995 O ILE A 126 60.920 55.440 11.948 1.00 28.24 A O ATOM 996 CB ILE A 126 58.878 53.883 10.690 1.00 31.52 A C ATOM 997 CG1 ILE A 126 59.197 54.235 9.234 1.00 28.75 A C ATOM 998 CG2 ILE A 126 57.699 52.908 10.764 1.00 31.40 A C ATOM 999 CD1 ILE A 126 59.677 53.053 8.429 1.00 29.82 A C ATOM 1000 N ALA A 127 59.751 57.298 11.493 1.00 26.38 A N ATOM 1001 CA ALA A 127 60.844 58.222 11.762 1.00 28.14 A C ATOM 1002 C ALA A 127 61.072 58.286 13.267 1.00 30.57 A C ATOM 1003 O ALA A 127 60.139 58.129 14.056 1.00 27.34 A O ATOM 1004 CB ALA A 127 60.516 59.588 11.228 1.00 26.20 A C ATOM 1005 N ARG A 128 62.323 58.479 13.650 1.00 32.29 A N ATOM 1006 CA ARG A 128 62.686 58.711 15.042 1.00 32.33 A C ATOM 1007 C ARG A 128 63.110 60.172 15.214 1.00 32.76 A C ATOM 1008 O ARG A 128 63.673 60.773 14.288 1.00 28.12 A O ATOM 1009 CB ARG A 128 63.775 57.748 15.468 1.00 33.84 A C ATOM 1010 CG ARG A 128 63.268 56.329 15.638 1.00 39.19 A C ATOM 1011 CD ARG A 128 64.006 55.302 14.843 1.00 43.32 A C ATOM 1012 NE ARG A 128 63.338 54.007 14.915 1.00 49.88 A N ATOM 1013 CZ ARG A 128 63.811 52.881 14.384 1.00 49.47 A C ATOM 1014 NH1 ARG A 128 63.115 51.757 14.508 1.00 52.74 A N ATOM 1015 NH2 ARG A 128 64.968 52.865 13.731 1.00 50.48 A N ATOM 1016 N PRO A 129 62.816 60.791 16.364 1.00 31.47 A N ATOM 1017 CA PRO A 129 62.218 60.159 17.553 1.00 34.71 A C ATOM 1018 C PRO A 129 60.705 59.942 17.479 1.00 34.15 A C ATOM 1019 O PRO A 129 60.172 59.122 18.229 1.00 37.59 A O ATOM 1020 CB PRO A 129 62.498 61.176 18.670 1.00 32.03 A C ATOM 1021 CG PRO A 129 62.887 62.461 18.005 1.00 33.32 A C ATOM 1022 CD PRO A 129 63.036 62.232 16.548 1.00 34.13 A C ATOM 1023 N ASP A 130 60.031 60.701 16.626 1.00 34.80 A N ATOM 1024 CA ASP A 130 58.604 60.519 16.390 1.00 38.13 A C ATOM 1025 C ASP A 130 58.234 60.967 14.976 1.00 36.50 A C ATOM 1026 O ASP A 130 59.075 61.471 14.227 1.00 36.70 A O ATOM 1027 CB ASP A 130 57.779 61.280 17.450 1.00 39.51 A C ATOM 1028 CG ASP A 130 58.154 62.756 17.558 1.00 44.22 A C ATOM 1029 OD1 ASP A 130 58.795 63.139 18.571 1.00 51.20 A O ATOM 1030 OD2 ASP A 130 57.839 63.614 16.705 1.00 44.98 A O ATOM 1031 N ASP A 131 56.963 60.814 14.623 1.00 38.18 A N ATOM 1032 CA ASP A 131 56.511 61.090 13.261 1.00 38.88 A C ATOM 1033 C ASP A 131 56.397 62.569 12.911 1.00 36.53 A C ATOM 1034 O ASP A 131 55.943 62.905 11.827 1.00 35.45 A O ATOM 1035 CB ASP A 131 55.191 60.346 12.950 1.00 39.38 A C ATOM 1036 CG ASP A 131 54.010 60.844 13.771 1.00 41.70 A C ATOM 1037 OD1 ASP A 131 54.067 61.976 14.296 1.00 42.89 A O ATOM 1038 OD2 ASP A 131 52.970 60.165 13.935 1.00 42.85 A O ATOM 1039 N SER A 132 56.801 63.462 13.815 1.00 37.22 A N ATOM 1040 CA SER A 132 56.825 64.891 13.495 1.00 34.53 A C ATOM 1041 C SER A 132 58.138 65.313 12.811 1.00 32.93 A C ATOM 1042 O SER A 132 58.242 66.415 12.301 1.00 31.50 A O ATOM 1043 CB SER A 132 56.569 65.733 14.753 1.00 36.86 A C ATOM 1044 OG SER A 132 57.784 66.236 15.282 1.00 41.97 A O ATOM 1045 N LEU A 133 59.142 64.442 12.800 1.00 33.79 A N ATOM 1046 CA LEU A 133 60.371 64.730 12.053 1.00 32.04 A C ATOM 1047 C LEU A 133 60.174 64.308 10.601 1.00 30.10 A C ATOM 1048 O LEU A 133 60.179 63.117 10.279 1.00 31.31 A O ATOM 1049 CB LEU A 133 61.586 64.035 12.652 1.00 30.30 A C ATOM 1050 CG LEU A 133 62.901 64.622 12.116 1.00 31.05 A C ATOM 1051 CD1 LEU A 133 63.289 65.900 12.891 1.00 30.64 A C ATOM 1052 CD2 LEU A 133 64.000 63.606 12.180 1.00 26.23 A C ATOM 1053 N GLU A 134 60.028 65.294 9.734 1.00 32.24 A N ATOM 1054 CA GLU A 134 59.630 65.044 8.362 1.00 30.89 A C ATOM 1055 C GLU A 134 60.812 64.398 7.611 1.00 30.52 A C ATOM 1056 O GLU A 134 61.938 64.919 7.650 1.00 27.23 A O ATOM 1057 CB GLU A 134 59.088 66.332 7.709 1.00 35.75 A C ATOM 1058 CG GLU A 134 59.723 66.804 6.414 1.00 41.00 A C ATOM 1059 CD GLU A 134 59.016 68.022 5.819 1.00 43.25 A C ATOM 1060 OE1 GLU A 134 59.719 68.930 5.302 1.00 45.72 A O ATOM 1061 OE2 GLU A 134 57.763 68.096 5.869 1.00 48.16 A O ATOM 1062 N PRO A 135 60.566 63.249 6.975 1.00 25.18 A N ATOM 1063 CA PRO A 135 61.581 62.606 6.119 1.00 24.30 A C ATOM 1064 C PRO A 135 62.039 63.453 4.958 1.00 19.94 A C ATOM 1065 O PRO A 135 61.337 64.319 4.481 1.00 23.86 A O ATOM 1066 CB PRO A 135 60.847 61.379 5.579 1.00 22.83 A C ATOM 1067 CG PRO A 135 59.796 61.109 6.573 1.00 25.70 A C ATOM 1068 CD PRO A 135 59.328 62.450 7.020 1.00 24.61 A C ATOM 1069 N PHE A 136 63.243 63.160 4.474 1.00 19.75 A N ATOM 1070 CA PHE A 136 63.850 63.848 3.367 1.00 20.77 A C ATOM 1071 C PHE A 136 62.945 64.000 2.166 1.00 25.10 A C ATOM 1072 O PHE A 136 62.798 65.099 1.632 1.00 23.63 A O ATOM 1073 CB PHE A 136 65.094 63.106 2.886 1.00 21.20 A C ATOM 1074 CG PHE A 136 65.704 63.716 1.669 1.00 19.23 A C ATOM 1075 CD1 PHE A 136 66.414 64.905 1.758 1.00 26.30 A C ATOM 1076 CD2 PHE A 136 65.522 63.144 0.421 1.00 23.32 A C ATOM 1077 CE1 PHE A 136 66.962 65.494 0.626 1.00 25.62 A C ATOM 1078 CE2 PHE A 136 66.078 63.727 −0.719 1.00 23.61 A C ATOM 1079 CZ PHE A 136 66.787 64.903 −0.615 1.00 29.48 A C ATOM 1080 N PHE A 137 62.402 62.886 1.694 1.00 21.94 A N ATOM 1081 CA PHE A 137 61.655 62.903 0.444 1.00 20.25 A C ATOM 1082 C PHE A 137 60.396 63.749 0.582 1.00 21.90 A C ATOM 1083 O PHE A 137 59.966 64.370 −0.379 1.00 24.14 A O ATOM 1084 CB PHE A 137 61.271 61.509 −0.026 1.00 18.67 A C ATOM 1085 CG PHE A 137 61.039 61.440 −1.491 1.00 20.54 A C ATOM 1086 CD1 PHE A 137 62.099 61.302 −2.361 1.00 23.22 A C ATOM 1087 CD2 PHE A 137 59.757 61.511 −2.003 1.00 22.93 A C ATOM 1088 CE1 PHE A 137 61.900 61.241 −3.721 1.00 27.68 A C ATOM 1089 CE2 PHE A 137 59.551 61.462 −3.374 1.00 20.33 A C ATOM 1090 CZ PHE A 137 60.616 61.334 −4.232 1.00 22.33 A C ATOM 1091 N ASP A 138 59.814 63.750 1.775 1.00 22.45 A N ATOM 1092 CA ASP A 138 58.649 64.582 2.081 1.00 25.79 A C ATOM 1093 C ASP A 138 59.020 66.055 1.966 1.00 27.43 A C ATOM 1094 O ASP A 138 58.296 66.825 1.326 1.00 30.80 A O ATOM 1095 CB ASP A 138 58.124 64.309 3.479 1.00 27.52 A C ATOM 1096 CG ASP A 138 57.419 62.982 3.596 1.00 33.12 A C ATOM 1097 OD1 ASP A 138 56.177 63.001 3.674 1.00 41.90 A O ATOM 1098 OD2 ASP A 138 58.004 61.870 3.644 1.00 36.84 A O ATOM 1099 N SER A 139 60.141 66.452 2.573 1.00 25.82 A N ATOM 1100 CA SER A 139 60.662 67.825 2.393 1.00 26.28 A C ATOM 1101 C SER A 139 60.957 68.169 0.940 1.00 26.44 A C ATOM 1102 O SER A 139 60.719 69.293 0.496 1.00 28.87 A O ATOM 1103 CB SER A 139 61.951 68.049 3.204 1.00 21.06 A C ATOM 1104 OG SER A 139 61.769 67.663 4.541 1.00 25.91 A O ATOM 1105 N LEU A 140 61.493 67.212 0.188 1.00 24.71 A N ATOM 1106 CA LEU A 140 61.816 67.443 −1.209 1.00 24.32 A C ATOM 1107 C LEU A 140 60.547 67.732 −2.019 1.00 26.78 A C ATOM 1108 O LEU A 140 60.555 68.649 −2.851 1.00 28.93 A O ATOM 1109 CB LEU A 140 62.555 66.253 −1.819 1.00 25.33 A C ATOM 1110 CG LEU A 140 62.797 66.212 −3.332 1.00 27.48 A C ATOM 1111 CD1 LEU A 140 63.903 67.142 −3.762 1.00 30.78 A C ATOM 1112 CD2 LEU A 140 63.124 64.795 −3.764 1.00 32.40 A C ATOM 1113 N VAL A 141 59.482 66.964 −1.774 1.00 27.82 A N ATOM 1114 CA VAL A 141 58.236 67.121 −2.539 1.00 27.51 A C ATOM 1115 C VAL A 141 57.548 68.440 −2.159 1.00 33.11 A C ATOM 1116 O VAL A 141 57.054 69.159 −3.024 1.00 34.42 A O ATOM 1117 CB VAL A 141 57.268 65.953 −2.319 1.00 30.35 A C ATOM 1118 CG1 VAL A 141 55.923 66.224 −2.980 1.00 31.75 A C ATOM 1119 CG2 VAL A 141 57.849 64.666 −2.885 1.00 30.79 A C ATOM 1120 N LYS A 142 57.541 68.747 −0.868 1.00 32.37 A N ATOM 1121 CA LYS A 142 56.876 69.931 −0.338 1.00 37.06 A C ATOM 1122 C LYS A 142 57.527 71.211 −0.828 1.00 34.32 A C ATOM 1123 O LYS A 142 56.826 72.191 −1.091 1.00 35.77 A O ATOM 1124 CB LYS A 142 56.876 69.897 1.187 1.00 37.65 A C ATOM 1125 CG LYS A 142 56.135 71.055 1.850 1.00 44.63 A C ATOM 1126 CD LYS A 142 55.689 70.702 3.264 1.00 46.28 A C ATOM 1127 CE LYS A 142 54.644 71.684 3.779 1.00 49.93 A C ATOM 1128 NZ LYS A 142 54.400 71.364 5.250 0.00 45.29 A N ATOM 1129 N GLN A 143 58.848 71.196 −0.999 1.00 30.71 A N ATOM 1130 CA GLN A 143 59.602 72.415 −1.260 1.00 32.98 A C ATOM 1131 C GLN A 143 59.948 72.655 −2.726 1.00 31.39 A C ATOM 1132 O GLN A 143 60.393 73.754 −3.071 1.00 35.65 A O ATOM 1133 CB GLN A 143 60.900 72.429 −0.443 1.00 29.67 A C ATOM 1134 CG GLN A 143 60.712 72.505 1.045 1.00 29.86 A C ATOM 1135 CD GLN A 143 62.033 72.359 1.785 1.00 22.99 A C ATOM 1136 OE1 GLN A 143 62.072 71.774 2.871 1.00 32.84 A O ATOM 1137 NE2 GLN A 143 63.100 72.879 1.202 1.00 24.10 A N ATOM 1138 N THR A 144 59.767 71.650 −3.588 1.00 30.44 A N ATOM 1139 CA THR A 144 60.095 71.786 −5.011 1.00 31.63 A C ATOM 1140 C THR A 144 58.950 71.268 −5.887 1.00 32.37 A C ATOM 1141 O THR A 144 57.910 70.882 −5.368 1.00 35.67 A O ATOM 1142 CB THR A 144 61.405 71.032 −5.365 1.00 35.08 A C ATOM 1143 OG1 THR A 144 61.169 69.613 −5.395 1.00 34.32 A O ATOM 1144 CG2 THR A 144 62.458 71.221 −4.298 1.00 34.68 A C ATOM 1145 N HIS A 145 59.165 71.247 −7.203 1.00 36.14 A N ATOM 1146 CA HIS A 145 58.193 70.682 −8.155 1.00 39.38 A C ATOM 1147 C HIS A 145 58.512 69.232 −8.562 1.00 37.43 A C ATOM 1148 O HIS A 145 57.961 68.715 −9.544 1.00 33.33 A O ATOM 1149 CB HIS A 145 58.097 71.563 −9.409 1.00 43.05 A C ATOM 1150 CG HIS A 145 57.493 72.910 −9.154 1.00 47.15 A C ATOM 1151 ND1 HIS A 145 56.200 73.072 −8.703 1.00 50.46 A N ATOM 1152 CD2 HIS A 145 58.006 74.157 −9.284 1.00 49.69 A C ATOM 1153 CE1 HIS A 145 55.941 74.361 −8.570 1.00 51.63 A C ATOM 1154 NE2 HIS A 145 57.021 75.041 −8.913 1.00 51.86 A N ATOM 1155 N VAL A 146 59.379 68.565 −7.798 1.00 33.76 A N ATOM 1156 CA VAL A 146 59.705 67.163 −8.059 1.00 29.14 A C ATOM 1157 C VAL A 146 58.472 66.301 −7.774 1.00 22.43 A C ATOM 1158 O VAL A 146 57.885 66.398 −6.697 1.00 24.83 A O ATOM 1159 CB VAL A 146 60.921 66.695 −7.206 1.00 27.14 A C ATOM 1160 CG1 VAL A 146 61.151 65.185 −7.339 1.00 27.28 A C ATOM 1161 CG2 VAL A 146 62.178 67.468 −7.626 1.00 26.85 A C ATOM 1162 N PRO A 147 58.045 65.483 −8.744 1.00 26.48 A N ATOM 1163 CA PRO A 147 56.864 64.637 −8.557 1.00 26.08 A C ATOM 1164 C PRO A 147 57.049 63.662 −7.403 1.00 22.97 A C ATOM 1165 O PRO A 147 58.185 63.217 −7.166 1.00 27.41 A O ATOM 1166 CB PRO A 147 56.749 63.885 −9.882 1.00 25.30 A C ATOM 1167 CG PRO A 147 57.462 64.717 −10.865 1.00 27.21 A C ATOM 1168 CD PRO A 147 58.636 65.310 −10.089 1.00 25.24 A C ATOM 1169 N ASN A 148 55.963 63.339 −6.711 1.00 21.69 A N ATOM 1170 CA ASN A 148 56.014 62.466 −5.551 1.00 21.05 A C ATOM 1171 C ASN A 148 56.167 60.969 −5.908 1.00 21.77 A C ATOM 1172 O ASN A 148 55.305 60.152 −5.607 1.00 21.62 A O ATOM 1173 CB ASN A 148 54.797 62.717 −4.670 1.00 23.86 A C ATOM 1174 CG ASN A 148 54.878 62.024 −3.338 1.00 22.10 A C ATOM 1175 OD1 ASN A 148 55.967 61.652 −2.885 1.00 20.69 A O ATOM 1176 ND2 ASN A 148 53.716 61.795 −2.710 1.00 25.43 A N ATOM 1177 N LEU A 149 57.291 60.629 −6.524 1.00 20.43 A N ATOM 1178 CA LEU A 149 57.666 59.252 −6.775 1.00 22.50 A C ATOM 1179 C LEU A 149 59.152 59.110 −7.020 1.00 21.20 A C ATOM 1180 O LEU A 149 59.838 60.073 −7.389 1.00 19.54 A O ATOM 1181 CB LEU A 149 56.859 58.654 −7.927 1.00 25.03 A C ATOM 1182 CG LEU A 149 57.349 58.789 −9.346 1.00 28.60 A C ATOM 1183 CD1 LEU A 149 56.502 57.899 −10.267 1.00 30.70 A C ATOM 1184 CD2 LEU A 149 57.237 60.237 −9.725 1.00 30.68 A C ATOM 1185 N PHE A 150 59.678 57.919 −6.745 1.00 18.27 A N ATOM 1186 CA PHE A 150 61.044 57.586 −7.149 1.00 18.21 A C ATOM 1187 C PHE A 150 61.116 56.104 −7.566 1.00 17.26 A C ATOM 1188 O PHE A 150 60.229 55.324 −7.235 1.00 17.41 A O ATOM 1189 CB PHE A 150 62.054 57.925 −6.045 1.00 16.20 A C ATOM 1190 CG PHE A 150 61.904 57.072 −4.808 1.00 15.43 A C ATOM 1191 CD1 PHE A 150 61.042 57.450 −3.805 1.00 18.11 A C ATOM 1192 CD2 PHE A 150 62.614 55.885 −4.681 1.00 17.12 A C ATOM 1193 CE1 PHE A 150 60.883 56.655 −2.694 1.00 16.60 A C ATOM 1194 CE2 PHE A 150 62.477 55.092 −3.564 1.00 16.66 A C ATOM 1195 CZ PHE A 150 61.588 55.468 −2.576 1.00 18.98 A C ATOM 1196 N SER A 151 62.143 55.741 −8.320 1.00 15.58 A N ATOM 1197 CA SER A 151 62.353 54.360 −8.764 1.00 13.42 A C ATOM 1198 C SER A 151 63.779 53.904 −8.612 1.00 15.43 A C ATOM 1199 O SER A 151 64.717 54.708 −8.638 1.00 17.96 A O ATOM 1200 CB SER A 151 61.880 54.171 −10.200 1.00 18.86 A C ATOM 1201 OG SER A 151 62.440 55.169 −11.021 1.00 19.88 A O ATOM 1202 N LEU A 152 63.932 52.603 −8.401 1.00 15.64 A N ATOM 1203 CA LEU A 152 65.213 51.992 −8.105 1.00 16.25 A C ATOM 1204 C LEU A 152 65.456 50.817 −9.015 1.00 17.29 A C ATOM 1205 O LEU A 152 64.596 49.925 −9.143 1.09 17.99 A O ATOM 1206 CB LEU A 152 65.248 51.493 −6.650 1.00 16.35 A C ATOM 1207 CG LEU A 152 65.317 52.590 −5.590 1.00 18.65 A C ATOM 1208 CD1 LEU A 152 65.177 51.994 −4.208 1.00 19.71 A C ATOM 1209 CD2 LEU A 152 66.585 53.418 −5.725 1.00 19.60 A C ATOM 1210 N GLN A 153 66.618 50.820 −9.646 1.00 19.70 A N ATOM 1211 CA GLN A 153 67.115 49.692 −10.419 1.00 19.09 A C ATOM 1212 C GLN A 153 68.422 49.296 −9.747 1.00 17.61 A C ATOM 1213 O GLN A 153 69.438 49.964 −9.921 1.00 22.26 A O ATOM 1214 CB GLN A 153 67.368 50.078 −11.883 1.00 23.44 A C ATOM 1215 CG GLN A 153 67.771 48.873 −12.721 1.00 24.58 A C ATOM 1216 CD GLN A 153 68.573 49.194 −13.957 1.00 26.89 A C ATOM 1217 OE1 GLN A 153 69.610 49.863 −13.895 1.00 32.38 A O ATOM 1218 NE2 GLN A 153 68.116 48.681 −15.089 1.00 27.76 A N ATOM 1219 N LEU A 154 68.392 48.247 −8.941 1.00 17.74 A N ATOM 1220 CA LEU A 154 69.618 47.726 −8.329 1.00 21.30 A C ATOM 1221 C LEU A 154 70.186 46.576 −9.166 1.00 28.90 A C ATOM 1222 O LEU A 154 69.479 45.609 −9.464 1.00 29.97 A O ATOM 1223 CB LEU A 154 69.339 47.276 −6.898 1.00 21.73 A C ATOM 1224 CG LEU A 154 68.556 48.277 −6.046 1.00 22.21 A C ATOM 1225 CD1 LEU A 154 68.239 47.712 −4.686 1.00 25.89 A C ATOM 1226 CD2 LEU A 154 69.266 49.619 −5.888 1.00 22.60 A C ATOM 1227 N CYS A 155 71.461 46.678 −9.537 1.00 32.67 A N ATOM 1228 CA CYS A 155 72.096 45.709 −10.442 1.00 36.54 A C ATOM 1229 C CYS A 155 73.103 44.805 −9.720 1.00 41.47 A C ATOM 1230 O CYS A 155 72.719 43.815 −9.116 1.00 43.64 A O ATOM 1231 CB CYS A 155 72.744 46.440 −11.616 1.09 36.93 A C ATOM 1232 SG CYS A 155 71.580 47.462 −12.528 1.00 37.02 A S ATOM 1233 N GLY A 156 74.389 45.122 −9.802 1.00 49.66 A N ATOM 1234 CA GLY A 156 75.416 44.312 −9.170 1.00 52.13 A C ATOM 1235 C GLY A 156 75.784 43.035 −9.897 1.00 54.64 A C ATOM 1226 O GLY A 156 75.586 41.937 −9.372 1.00 55.03 A O ATOM 1237 N ALA A 157 76.323 43.196 −11.106 1.00 58.96 A N ATOM 1238 CA ALA A 157 76.935 42.104 −11.872 1.00 59.70 A C ATOM 1239 C ALA A 157 76.142 40.799 −11.808 1.00 61.26 A C ATOM 1240 O ALA A 157 76.543 39.845 −11.131 1.00 63.37 A O ATOM 1241 CB ALA A 157 78.377 41.881 −11.396 1.00 61.07 A C ATOM 1242 N ALA A 168 81.887 41.703 −5.577 1.00 52.10 A N ATOM 1243 CA ALA A 168 82.673 42.857 −6.011 1.00 51.66 A C ATOM 1244 C ALA A 168 81.807 44.132 −6.026 1.00 49.66 A C ATOM 1245 O ALA A 168 80.833 44.234 −5.270 1.00 47.62 A O ATOM 1246 CB ALA A 168 83.302 42.585 −7.389 1.00 52.14 A C ATOM 1247 N SER A 169 82.169 45.100 −6.865 1.00 48.50 A N ATOM 1248 CA SER A 169 81.455 46.373 −6.933 1.00 47.11 A C ATOM 1249 C SER A 169 80.128 46.241 −7.693 1.00 45.49 A C ATOM 1250 O SER A 169 80.102 45.793 −8.833 1.00 42.21 A O ATOM 1251 CB SER A 169 82.336 47.432 −7.596 1.00 48.06 A C ATOM 1252 OG SER A 169 81.625 48.637 −7.812 1.00 53.03 A O ATOM 1253 N VAL A 170 79.036 46.648 −7.048 1.00 40.36 A N ATOM 1254 CA VAL A 170 77.714 46.662 −7.675 1.00 36.88 A C ATOM 1255 C VAL A 170 77.329 48.074 −8.121 1.00 33.45 A C ATOM 1256 O VAL A 170 77.980 49.050 −7.751 1.00 27.09 A O ATOM 1257 CB VAL A 170 76.636 46.100 −6.714 1.00 35.68 A C ATOM 1258 CG1 VAL A 170 76.978 44.662 −6.301 1.00 38.27 A C ATOM 1259 CG2 VAL A 170 76.471 46.986 −5.476 1.00 36.83 A C ATOM 1260 N GLY A 171 76.256 48.174 −8.905 1.00 30.02 A N ATOM 1261 CA GLY A 171 75.760 49.457 −9.360 1.00 28.27 A C ATOM 1262 C GLV A 171 74.250 49.511 −9.521 1.00 23.99 A C ATOM 1263 O GLY A 171 73.567 48.502 −9.456 1.00 30.07 A O ATOM 1264 N GLY A 172 73.748 50.704 −9.785 1.00 22.93 A N ATOM 1265 CA GLY A 172 72.321 50.912 −9.960 1.00 24.79 A C ATOM 1266 C GLY A 172 71.921 52.328 −10.318 1.00 21.72 A C ATOM 1267 O GLY A 172 72.755 53.177 −10.586 1.00 20.97 A O ATOM 1268 N SER A 173 70.615 52.576 −10.323 1.00 20.55 A N ATOM 1269 CA SER A 173 70.056 53.881 −10.618 1.00 19.75 A C ATOM 1270 C SER A 173 68.934 54.169 −9.642 1.00 17.92 A C ATOM 1271 O SER A 173 68.098 53.318 −9.396 1.00 19.13 A O ATOM 1272 CB SER A 173 69.490 53.959 −12.045 1.00 20.34 A C ATOM 1273 OG SER A 173 70.498 53.718 −13.025 1.00 23.31 A O ATOM 1274 N MET A 174 68.935 55.371 −9.085 1.09 19.22 A N ATOM 1275 CA MET A 174 67.794 55.904 −8.368 1.00 19.42 A C ATOM 1276 C MET A 174 67.284 57.099 −9.164 1.00 20.07 A C ATOM 1277 O MET A 174 67.936 58.150 −9.226 1.00 18.63 A O ATOM 1278 CB MET A 174 68.156 56.332 −6.953 1.00 19.01 A C ATOM 1279 CG MET A 174 66.982 56.914 −6.230 1.00 22.45 A C ATOM 1280 SD MET A 174 67.349 57.388 −4.532 1.00 24.52 A S ATOM 1281 CE MET A 174 68.659 58.440 −4.766 1.00 27.89 A C ATOM 1282 N ILE A 175 66.135 56.904 −9.818 1.00 21.08 A N ATOM 1283 CA ILE A 175 65.469 57.972 −10.548 1.00 16.99 A C ATOM 1284 C ILE A 175 64.484 58.690 −9.642 1.00 16.84 A C ATOM 1285 O ILE A 175 63.468 58.119 −9.242 1.00 19.54 A O ATOM 1286 CB ILE A 175 64.740 57.415 −11.800 1.00 22.71 A C ATOM 1287 CG1 ILE A 175 65.645 56.492 −12.632 1.00 21.64 A C ATOM 1288 CG2 ILE A 175 64.160 58.559 −12.633 1.00 22.47 A C ATOM 1289 CD1 ILE A 175 66.942 57.124 −13.192 1.00 21.34 A C ATOM 1290 N ILE A 176 64.820 59.929 −9.276 1.00 22.11 A N ATOM 1291 CA ILE A 176 64.012 60.750 −8.396 1.00 22.51 A C ATOM 1292 C ILE A 176 63.045 61.581 −9.230 1.00 23.28 A C ATOM 1293 O ILE A 176 63.464 62.397 −10.056 1.00 27.99 A O ATOM 1294 CB ILE A 176 64.908 61.703 −7.567 1.00 24.59 A C ATOM 1295 CG1 ILE A 176 65.914 60.917 −6.718 1.00 27.72 A C ATOM 1296 CG2 ILE A 176 64.059 62.601 −6.699 1.00 26.83 A C ATOM 1297 CD1 ILE A 176 65.274 60.104 −5.618 1.00 30.97 A C ATOM 1298 N GLY A 177 61.762 61.359 −9.003 1.00 23.04 A N ATOM 1299 CA GLY A 177 60.711 62.169 −9.578 1.00 23.58 A C ATOM 1300 C GLY A 177 60.114 61.540 −10.810 1.00 27.69 A C ATOM 1301 O GLY A 177 59.224 62.125 −11.428 1.00 29.57 A O ATOM 1302 N GLY A 178 60.561 60.340 −11.160 1.00 24.14 A N ATOM 1303 CA GLY A 178 60.023 59.706 −12.342 1.00 26.72 A C ATOM 1304 C GLY A 178 60.460 58.295 −12.586 1.00 27.37 A C ATOM 1305 O GLY A 178 61.017 57.610 −11.712 1.00 24.67 A O ATOM 1306 N ILE A 179 60.153 57.861 −13.800 1.00 24.35 A N ATOM 1307 CA ILE A 179 60.475 56.541 −14.300 1.00 28.10 A C ATOM 1308 C ILE A 179 61.277 56.703 −15.591 1.00 30.00 A C ATOM 1309 O ILE A 179 61.031 57.640 −16.367 1.00 29.66 A O ATOM 1310 CB ILE A 179 59.174 55.751 −14.552 1.00 28.71 A C ATOM 1311 CG1 ILE A 179 58.240 55.833 −13.314 1.00 31.09 A C ATOM 1312 CG2 ILE A 179 59.480 54.319 −14.890 1.00 32.54 A C ATOM 1313 CD1 ILE A 179 56.941 55.086 −13.456 1.00 35.50 A C ATOM 1314 N ASP A 180 62.241 55.806 −15.795 1.00 29.78 A N ATOM 1315 CA ASP A 180 63.094 55.783 −16.983 1.00 32.20 A C ATOM 1316 C ASP A 180 62.895 54.450 −17.703 1.00 30.45 A C ATOM 1317 O ASP A 180 63.345 53.399 −17.240 1.00 27.79 A O ATOM 1318 CB ASP A 180 64.566 55.955 −16.576 1.00 31.37 A C ATOM 1319 CG ASP A 180 65.488 56.151 −17.759 1.00 37.38 A C ATOM 1320 OD1 ASP A 180 65.155 55.692 −18.868 1.00 40.09 A O ATOM 1321 OD2 ASP A 180 66.577 56.746 −17.670 1.00 37.04 A O ATOM 1322 N HIS A 181 62.235 54.504 −18.856 1.00 34.60 A N ATOM 1323 CA HIS A 181 61.829 53.298 −19.592 1.00 34.97 A C ATOM 1324 C HIS A 181 62.986 52.434 −20.108 1.00 35.24 A C ATOM 1325 O HIS A 181 62.825 51.229 −20.323 1.00 34.58 A O ATOM 1326 CB HIS A 181 60.868 53.695 −20.721 1.00 38.80 A C ATOM 1327 CG HIS A 181 59.662 54.442 −20.233 0.50 38.66 A C ATOM 1328 ND1 HIS A 181 58.846 53.959 −19.234 0.50 38.35 A N ATOM 1329 CD2 HIS A 181 59.158 55.649 −20.580 0.50 40.41 A C ATOM 1330 CE1 HIS A 181 57.880 54.828 −18.998 0.50 40.15 A C ATOM 1331 NE2 HIS A 181 58.045 55.863 −19.803 0.50 40.15 A N ATOM 1332 N SER A 182 64.167 53.026 −20.244 1.00 33.98 A N ATOM 1333 CA SER A 182 65.369 52.269 −20.589 1.00 34.19 A C ATOM 1334 C SER A 182 65.834 51.304 −19.484 1.00 31.16 A C ATOM 1335 O SER A 182 66.638 50.418 −19.736 1.00 29.95 A O ATOM 1336 CB SER A 182 66.507 53.230 −20.966 1.00 36.56 A C ATOM 1337 OG SER A 182 66.853 54.088 −19.886 1.00 39.80 A O ATOM 1338 N LEU A 183 65.318 51.458 −18.261 1.00 28.19 A N ATOM 1339 CA LEU A 183 65.719 50.607 −17.156 1.00 26.88 A C ATOM 1340 C LEU A 183 64.920 49.310 −17.012 1.00 26.28 A C ATOM 1341 O LEU A 183 65.267 48.479 −16.178 1.00 21.62 A O ATOM 1342 CB LEU A 183 65.646 51.397 −15.838 1.00 26.71 A C ATOM 1343 CG LEU A 183 66.557 52.620 −15.805 1.00 30.09 A C ATOM 1344 CD1 LEU A 183 66.413 53.360 −14.479 1.00 28.34 A C ATOM 1345 CD2 LEU A 183 67.997 52.185 −16.027 1.00 33.43 A C ATOM 1346 N TYR A 184 63.865 49.130 −17.822 1.00 26.39 A N ATOM 1347 CA TYR A 184 63.038 47.935 −17.710 1.00 22.78 A C ATOM 1348 C TYR A 184 62.486 47.453 −19.040 1.00 22.69 A C ATOM 1349 O TYR A 184 62.380 48.227 −19.990 1.00 23.92 A O ATOM 1350 CB TYR A 184 61.856 48.135 −16.742 1.00 22.73 A C ATOM 1351 CG TYR A 184 60.726 49.040 −17.193 1.00 20.79 A C ATOM 1352 CD1 TYR A 184 59.540 48.523 −17.735 1.00 21.72 A C ATOM 1353 CD2 TYR A 184 60.812 50.410 −17.035 1.00 23.49 A C ATOM 1354 CE1 TYR A 184 58.500 49.357 −18.123 1.00 23.85 A C ATOM 1355 CE2 TYR A 184 59.776 51.250 −17.395 1.00 21.72 A C ATOM 1356 CZ TYR A 184 58.616 50.718 −17.949 1.00 23.96 A C ATOM 1357 OH TYR A 184 57.603 51.567 −18.306 1.00 27.89 A O ATOM 1358 N THR A 185 62.082 46.190 −19.048 1.00 26.60 A N ATOM 1359 CA THR A 185 61.397 45.590 −20.194 1.00 23.12 A C ATOM 1360 C THR A 185 60.012 45.120 −19.777 1.00 26.64 A C ATOM 1361 O THR A 185 59.754 44.849 −18.608 1.00 24.65 A O ATOM 1362 CB THR A 185 62.215 44.414 −20.801 1.00 25.79 A C ATOM 1363 OG1 THR A 185 62.261 43.299 −19.906 1.00 28.94 A O ATOM 1364 CG2 THR A 185 63.702 44.791 −20.980 1.00 32.36 A C ATOM 1365 N GLY A 186 59.127 44.998 −20.762 1.00 30.22 A N ATOM 1366 CA GLY A 186 57.765 44.602 −20.489 1.00 28.03 A C ATOM 1367 C GLY A 186 57.019 45.726 −19.805 1.00 24.17 A C ATOM 1368 O GLY A 186 57.380 46.894 −19.927 1.00 29.37 A O ATOM 1369 N SER A 187 55.952 45.365 −19.102 1.00 23.81 A N ATOM 1370 CA SER A 187 55.062 46.328 −18.488 1.00 21.71 A C ATOM 1371 C SER A 187 55.311 46.342 −16.996 1.00 19.66 A C ATOM 1372 O SER A 187 55.732 45.342 −16.426 1.00 20.42 A O ATOM 1373 CB SER A 187 53.601 45.940 −18.750 1.00 23.20 A C ATOM 1374 OG SER A 187 52.695 46.740 −18.000 1.00 25.16 A O ATOM 1375 N LEU A 188 55.046 47.493 −16.390 1.00 18.89 A N ATOM 1376 CA LEU A 188 54.965 47.608 −14.928 1.00 17.77 A C ATOM 1377 C LEU A 188 53.629 47.054 −14.466 1.00 19.39 A C ATOM 1378 O LEU A 188 52.601 47.299 −15.082 1.00 21.63 A O ATOM 1379 CB LEU A 188 55.067 49.054 −14.470 1.00 18.74 A C ATOM 1380 CG LEU A 188 56.433 49.736 −14.522 1.00 18.45 A C ATOM 1381 CD1 LEU A 188 56.311 51.222 −14.556 1.00 20.69 A C ATOM 1382 CD2 LEU A 188 57.295 49.273 −13.305 1.00 19.48 A C ATOM 1383 N TRP A 189 53.670 46.295 −13.384 1.00 13.99 A N ATOM 1384 CA TRP A 189 52.524 45.838 −12.633 1.00 15.66 A C ATOM 1385 C TRP A 189 52.595 46.453 −11.245 1.00 16.26 A C ATOM 1386 O TRP A 189 53.650 46.442 −10.633 1.00 17.41 A O ATOM 1387 CB TRP A 189 52.542 44.325 −12.516 1.00 15.88 A C ATOM 1388 CG TRP A 189 52.121 43.681 −13.817 1.00 18.59 A C ATOM 1389 CD1 TRP A 189 52.916 43.461 −14.898 1.00 21.85 A C ATOM 1390 CD2 TRP A 189 50.800 43.262 −14.200 1.00 18.24 A C ATOM 1391 NE1 TRP A 189 52.189 42.888 −15.919 1.00 23.05 A N ATOM 1392 CE2 TRP A 189 50.885 42.772 −15.522 1.00 19.78 A C ATOM 1393 CE3 TRP A 189 49.552 43.264 −13.570 1.00 15.96 A C ATOM 1394 CZ2 TRP A 189 49.777 42.292 −16.224 1.00 20.18 A C ATOM 1395 CZ3 TRP A 189 48.436 42.778 −14.274 1.00 17.80 A C ATOM 1396 CH2 TRP A 189 48.570 42.298 −15.590 1.00 16.72 A C ATOM 1397 N TYR A 190 51.467 46.920 −10.739 1.00 14.59 A N ATOM 1398 CA TYR A 190 51.425 47.625 −9.453 1.00 14.85 A C ATOM 1399 C TYR A 190 50.631 46.901 −8.353 1.00 17.95 A C ATOM 1400 O TYR A 190 49.564 46.289 −8.586 1.00 13.30 A O ATOM 1401 CB TYR A 190 50.864 49.021 −9.636 1.00 13.88 A C ATOM 1402 CG TYR A 190 51.635 49.973 −10.515 1.00 15.59 A C ATOM 1403 CD1 TYR A 190 52.573 50.842 −9.977 1.00 15.38 A C ATOM 1404 CD2 TYR A 190 51.339 50.092 −11.866 1.00 17.42 A C ATOM 1405 CE1 TYR A 190 53.237 51.770 −10.760 1.00 17.56 A C ATOM 1406 CE2 TYR A 190 52.018 51.038 −12.685 1.00 14.93 A C ATOM 1407 CZ TYR A 190 52.954 51.873 −12.107 1.00 18.74 A C ATOM 1408 OH TYR A 190 53.638 52.785 −12.865 1.00 17.23 A O ATOM 1409 N THR A 191 51.182 46.980 −7.139 1.00 16.74 A N ATOM 1410 CA THR A 191 50.568 46.429 −5.953 1.00 15.64 A C ATOM 1411 C THR A 191 50.304 47.626 −5.008 1.00 17.89 A C ATOM 1412 O THR A 191 51.106 48.544 −4.975 1.00 16.52 A O ATOM 1413 CB THR A 191 51.520 45.392 −5.357 1.00 16.95 A C ATOM 1414 OG1 THR A 191 50.861 44.672 −4.325 1.00 19.32 A O ATOM 1415 CG2 THR A 191 52.768 46.057 −4.680 1.00 16.37 A C ATOM 1416 N PRO A 192 49.168 47.686 −4.309 1.00 20.12 A N ATOM 1417 CA PRO A 192 48.944 48.801 −3.365 1.00 21.23 A C ATOM 1418 C PRO A 192 49.911 48.871 −2.178 1.00 17.60 A C ATOM 1419 O PRO A 192 50.370 47.856 −1.643 1.00 24.36 A O ATOM 1420 CB PRO A 192 47.504 48.585 −2.876 1.00 21.11 A C ATOM 1421 CG PRO A 192 46.881 47.748 −3.955 1.00 22.26 A C ATOM 1422 CD PRO A 192 47.980 46.828 −4.424 1.00 23.51 A C ATOM 1423 N ILE A 193 50.235 50.099 −1.797 1.00 21.72 A N ATOM 1424 CA ILE A 193 50.881 50.339 −0.515 1.00 22.71 A C ATOM 1425 C ILE A 193 49.758 50.230 0.508 1.00 23.63 A C ATOM 1426 O ILE A 193 48.881 51.079 0.568 1.00 29.68 A O ATOM 1427 CB ILE A 193 51.550 51.713 −0.453 1.00 24.36 A C ATOM 1428 CG1 ILE A 193 52.730 51.781 −1.438 1.00 24.14 A C ATOM 1429 CG2 ILE A 193 52.036 51.993 0.987 1.00 24.12 A C ATOM 1430 CD1 ILE A 193 53.313 53.171 −1.629 1.00 22.49 A C ATOM 1431 N ARG A 194 49.764 49.145 1.257 1.00 29.07 A N ATOM 1432 CA ARG A 194 48.696 48.887 2.199 1.00 32.57 A C ATOM 1433 C ARG A 194 48.547 50.005 3.219 1.00 33.92 A C ATOM 1434 O ARG A 194 47.446 50.517 3.435 1.00 36.50 A O ATOM 1435 CB ARG A 194 48.940 47.592 2.930 1.00 31.65 A C ATOM 1436 CG ARG A 194 47.768 47.245 3.797 1.00 32.32 A C ATOM 1437 CD ARG A 194 48.031 46.137 4.719 1.00 34.05 A C ATOM 1438 NE ARG A 194 46.832 45.833 5.482 1.00 37.69 A N ATOM 1439 CZ ARG A 194 46.774 44.914 6.424 1.00 43.49 A C ATOM 1440 NH1 ARG A 194 47.853 44.211 6.726 1.00 45.66 A N ATOM 1441 NH2 ARG A 194 45.636 44.700 7.079 1.00 44.35 A N ATOM 1442 N ARG A 195 49.668 50.353 3.839 1.00 35.28 A N ATOM 1443 CA ARG A 195 49.740 51.436 4.817 1.00 35.11 A C ATOM 1444 C ARG A 195 51.059 52.190 4.631 1.00 32.34 A C ATOM 1445 O ARG A 195 52.089 51.576 4.401 1.00 28.84 A O ATOM 1446 CB ARG A 195 49.683 50.857 6.226 1.00 35.59 A C ATOM 1447 CG ARG A 195 49.645 51.910 7.339 1.00 40.30 A C ATOM 1448 CD ARG A 195 48.907 51.460 8.591 1.00 43.51 A C ATOM 1449 NE ARG A 195 49.734 50.619 9.458 1.00 44.69 A N ATOM 1450 CZ ARG A 195 50.582 51.069 10.387 1.00 46.19 A C ATOM 1451 NH1 ARG A 195 50.753 52.371 10.585 1.00 46.87 A N ATOM 1452 NH2 ARG A 195 51.274 50.201 11.124 1.00 46.12 A N ATOM 1453 N GLU A 196 51.016 53.508 4.766 1.00 33.16 A N ATOM 1454 CA GLU A 196 52.167 54.353 4.500 1.00 34.04 A C ATOM 1455 C GLU A 196 52.963 54.554 5.774 1.00 31.83 A C ATOM 1456 O GLU A 196 52.790 55.566 6.460 1.00 35.74 A O ATOM 1457 CB GLU A 196 51.728 55.699 3.953 1.00 33.34 A C ATOM 1458 CG GLU A 196 50.986 55.643 2.624 1.00 38.79 A C ATOM 1459 CD GLU A 196 50.230 56.927 2.341 1.00 42.74 A C ATOM 1460 OE1 GLU A 196 49.199 57.182 3.009 1.00 47.60 A O ATOM 1461 OE2 GLU A 196 50.661 57.688 1.450 1.00 42.51 A O ATOM 1462 N TRP A 197 53.805 53.567 6.075 1.00 29.99 A N ATOM 1463 CA TRP A 197 54.773 53.629 7.184 1.00 32.01 A C ATOM 1464 C TRP A 197 56.104 53.059 6.668 1.00 29.04 A C ATOM 1465 O TRP A 197 56.938 53.829 6.210 1.00 30.54 A O ATOM 1466 CB TRP A 197 54.229 52.970 8.474 1.00 31.92 A C ATOM 1467 CG TRP A 197 53.800 51.538 8.412 1.00 36.08 A C ATOM 1468 CD1 TRP A 197 53.091 50.926 7.418 1.00 36.38 A C ATOM 1469 CD2 TRP A 197 54.023 50.532 9.414 1.00 40.65 A C ATOM 1470 NE1 TRP A 197 52.887 49.605 7.726 1.00 40.70 A N ATOM 1471 CE2 TRP A 197 53.446 49.337 8.948 1.00 41.77 A C ATOM 1472 CE3 TRP A 197 54.672 50.518 10.658 1.00 41.22 A C ATOM 1473 CZ2 TRP A 197 53.486 48.146 9.680 1.00 43.13 A C ATOM 1474 CZ3 TRP A 197 54.720 49.337 11.381 1.00 40.93 A C ATOM 1475 CH2 TRP A 197 54.129 48.166 10.891 1.00 42.69 A C ATOM 1476 N TYR A 198 56.303 51.746 6.699 1.00 24.59 A N ATOM 1477 CA TYR A 198 57.184 51.077 5.740 1.00 25.69 A C ATOM 1478 C TYR A 198 56.456 51.094 4.391 1.00 22.71 A C ATOM 1479 O TYR A 198 55.317 51.519 4.305 1.00 25.15 A O ATOM 1480 CB TYR A 198 57.455 49.620 6.110 1.00 28.07 A C ATOM 1481 CG TYR A 198 58.137 49.394 7.453 1.00 32.69 A C ATOM 1482 CD1 TYR A 198 59.514 49.273 7.541 1.00 36.04 A C ATOM 1483 CD2 TYR A 198 57.393 49.289 8.627 1.00 35.45 A C ATOM 1484 CE1 TYR A 198 60.146 49.054 8.769 1.00 35.82 A C ATOM 1485 CE2 TYR A 198 58.015 49.079 9.865 1.00 36.80 A C ATOM 1486 CZ TYR A 198 59.385 48.962 9.927 1.00 38.75 A C ATOM 1487 OH TYR A 198 60.007 48.744 11.143 1.00 38.81 A O ATOM 1488 N TYR A 199 57.142 50.654 3.347 1.00 21.11 A N ATOM 1489 CA TYR A 199 56.497 50.364 2.048 1.00 21.41 A C ATOM 1490 C TYR A 199 55.866 48.991 2.152 1.00 18.46 A C ATOM 1491 O TYR A 199 56.471 47.969 1.784 1.00 18.42 A O ATOM 1492 CB TYR A 199 57.521 50.484 0.914 1.00 21.15 A C ATOM 1493 CG TYR A 199 57.861 51.927 0.640 1.00 18.31 A C ATOM 1494 CD1 TYR A 199 56.965 52.770 −0.020 1.00 17.27 A C ATOM 1495 CD2 TYR A 199 59.078 52.478 1.059 1.00 17.06 A C ATOM 1496 CE1 TYR A 199 57.275 54.106 −0.239 1.00 18.14 A C ATOM 1497 CE2 TYR A 199 59.394 53.799 0.816 1.00 14.53 A C ATOM 1498 CZ TYR A 199 58.510 54.608 0.178 1.00 17.63 A C ATOM 1499 OH TYR A 199 58.822 55.911 −0.024 1.00 17.71 A O ATOM 1500 N GLU A 200 54.664 48.979 2.742 1.00 21.57 A N ATOM 1501 CA GLU A 200 54.004 47.722 3.098 1.00 22.77 A C ATOM 1502 C GLU A 200 53.206 47.182 1.904 1.00 16.75 A C ATOM 1503 O GLU A 200 52.457 47.916 1.322 1.00 24.39 A O ATOM 1504 CB GLU A 200 53.030 47.909 4.260 1.00 24.90 A C ATOM 1505 CG GLU A 200 52.680 46.604 4.946 1.00 27.85 A C ATOM 1506 CD GLU A 200 51.514 46.716 5.919 1.00 28.16 A C ATOM 1507 OE1 GLU A 200 51.081 47.840 6.278 1.00 35.16 A O ATOM 1508 OE2 GLU A 200 50.987 45.649 6.300 1.00 34.56 A O ATOM 1509 N VAL A 201 53.386 45.920 1.596 1.00 22.87 A N ATOM 1510 CA VAL A 201 52.595 45.240 0.554 1.00 21.15 A C ATOM 1511 C VAL A 201 52.057 43.892 1.045 1.00 26.77 A C ATOM 1512 O VAL A 201 52.462 43.402 2.103 1.00 26.68 A O ATOM 1513 CB VAL A 201 53.455 44.997 −0.684 1.00 22.52 A C ATOM 1514 CG1 VAL A 201 54.012 46.314 −1.198 1.00 22.34 A C ATOM 1515 CG2 VAL A 201 54.593 43.991 −0.400 1.00 23.70 A C ATOM 1516 N ILE A 202 51.187 43.262 0.248 1.00 20.41 A N ATOM 1517 CA ILE A 202 50.579 41.984 0.632 1.00 24.08 A C ATOM 1518 C ILE A 262 50.901 40.908 −0.404 1.00 23.18 A C ATOM 1519 O ILE A 202 50.569 41.064 −1.572 1.00 21.92 A O ATOM 1520 CB ILE A 202 49.041 42.119 0.801 1.00 24.91 A C ATOM 1521 CG1 ILE A 202 48.697 43.058 1.967 1.00 28.97 A C ATOM 1522 CG2 ILE A 202 48.410 40.742 1.042 1.00 26.55 A C ATOM 1523 CD1 ILE A 202 47.237 43.384 2.081 1.00 28.35 A C ATOM 1524 N ILE A 203 51.552 39.836 0.037 1.00 20.58 A N ATOM 1525 CA ILE A 203 51.806 38.642 −0.749 1.00 23.06 A C ATOM 1526 C ILE A 203 50.600 37.712 −0.588 1.00 23.74 A C ATOM 1527 O ILE A 203 50.113 37.480 0.521 1.00 25.10 A O ATOM 1528 CB ILE A 203 53.097 37.940 −0.293 1.00 24.14 A C ATOM 1529 CG1 ILE A 203 54.310 38.807 −0.656 1.00 25.32 A C ATOM 1530 CG2 ILE A 203 53.196 36.561 −0.924 1.00 23.21 A C ATOM 1531 CD1 ILE A 203 55.655 38.280 −0.193 1.00 30.24 A C ATOM 1532 N VAL A 204 50.065 37.249 −1.705 1.00 24.79 A N ATOM 1533 CA VAL A 204 48.827 36.465 −1.685 1.00 22.84 A C ATOM 1534 C VAL A 204 49.050 34.992 −2.011 1.00 27.15 A C ATOM 1535 O VAL A 204 48.192 34.158 −1.721 1.00 28.57 A O ATOM 1536 CB VAL A 204 47.764 37.091 −2.640 1.00 21.80 A C ATOM 1537 CG1 VAL A 204 47.505 38.524 −2.253 1.00 20.60 A C ATOM 1538 CG2 VAL A 204 48.210 36.970 −4.075 1.00 24.51 A C ATOM 1539 N ARG A 205 50.191 34.678 −2.612 1.00 24.48 A N ATOM 1540 CA ARG A 205 50.540 33.330 −3.018 1.00 27.35 A C ATOM 1541 C ARG A 205 52.049 33.204 −3.207 1.00 32.98 A C ATOM 1542 O ARG A 205 52.755 34.167 −3.563 1.00 24.15 A O ATOM 1543 CB ARG A 205 49.815 32.977 −4.325 1.00 30.35 A C ATOM 1544 CG ARG A 205 49.857 31.540 −4.763 1.00 33.44 A C ATOM 1545 CD ARG A 205 49.122 31.314 −6.095 1.00 36.40 A C ATOM 1546 NE ARG A 205 49.502 30.060 −6.747 1.00 40.66 A N ATOM 1547 CZ ARG A 205 48.730 28.978 −6.838 1.00 44.96 A C ATOM 1548 NH1 ARG A 205 47.510 28.961 −6.312 1.00 49.55 A N ATOM 1549 NH2 ARG A 205 49.185 27.893 −7.457 1.00 48.81 A N ATOM 1550 N VAL A 206 52.548 32.004 −2.961 1.00 31.90 A N ATOM 1551 CA VAL A 206 53.955 31.713 −3.133 1.00 31.00 A C ATOM 1552 C VAL A 206 54.077 30.348 −3.747 1.00 36.19 A C ATOM 1553 O VAL A 206 53.523 29.380 −3.227 1.00 37.64 A O ATOM 1554 CB VAL A 206 54.727 31.762 −1.786 1.00 34.34 A C ATOM 1555 CG1 VAL A 206 56.208 31.653 −2.026 1.00 38.60 A C ATOM 1556 CG2 VAL A 206 54.407 33.029 −1.020 1.00 34.28 A C ATOM 1557 N GLU A 207 54.746 30.296 −4.889 1.00 35.57 A N ATOM 1558 CA GLU A 207 55.129 29.059 −5.525 1.00 40.01 A C ATOM 1559 C GLU A 207 56.630 28.880 −5.382 1.00 43.14 A C ATOM 1560 O GLU A 207 57.371 29.858 −5.263 1.00 38.43 A O ATOM 1561 CB GLU A 207 54.766 29.102 −7.007 1.00 41.74 A C ATOM 1562 CG GLU A 207 53.270 29.123 −7.274 1.00 41.66 A C ATOM 1563 CD GLU A 207 52.934 29.348 −8.733 1.00 41.56 A C ATOM 1564 OE1 GLU A 207 53.854 29.540 −9.548 1.00 40.42 A O ATOM 1565 OE2 GLU A 207 51.733 29.347 −9.071 1.00 47.50 A O ATOM 1566 N ILE A 208 57.063 27.620 −5.371 1.00 44.90 A N ATOM 1567 CA ILE A 208 58.462 27.260 −5.592 1.00 48.28 A C ATOM 1568 C ILE A 208 58.488 26.248 −6.737 1.00 50.10 A C ATOM 1569 O ILE A 208 57.926 25.155 −6.628 1.00 48.21 A O ATOM 1570 CB ILE A 208 59.106 26.692 −4.312 1.00 48.76 A C ATOM 1571 CG1 ILE A 208 59.185 27.770 −3.227 1.00 50.92 A C ATOM 1572 CG2 ILE A 208 60.499 26.179 −4.607 1.00 50.10 A C ATOM 1573 CD1 ILE A 208 59.221 27.225 −1.835 1.00 52.20 A C ATOM 1574 N ASN A 209 59.102 26.647 −7.846 1.00 51.40 A N ATOM 1575 CA ASN A 209 59.111 25.882 −9.091 1.00 56.38 A C ATOM 1576 C ASN A 209 57.756 25.851 −9.827 1.00 56.68 A C ATOM 1577 O ASN A 209 57.689 25.425 −10.982 1.00 55.91 A O ATOM 1578 CB ASN A 209 59.636 24.456 −8.847 1.00 58.04 A C ATOM 1579 CG ASN A 209 60.332 23.865 −10.064 1.00 60.28 A C ATOM 1580 OD1 ASN A 209 60.251 22.656 −10.316 1.00 65.04 A O ATOM 1581 ND2 ASN A 209 61.025 24.707 −10.820 1.00 62.80 A N ATOM 1582 N GLY A 210 56.696 26.338 −9.181 1.00 56.56 A N ATOM 1583 CA GLY A 210 55.345 26.202 −9.699 1.00 56.62 A C ATOM 1584 C GLY A 210 54.374 25.584 −8.708 1.00 57.30 A C ATOM 1585 O GLY A 210 53.169 25.564 −8.959 1.00 58.65 A O ATOM 1586 N GLN A 211 54.885 25.094 −7.582 1.00 56.04 A N ATOM 1587 CA GLN A 211 54.071 24.409 −6.589 1.00 56.19 A C ATOM 1588 C GLN A 211 53.873 25.311 −5.383 1.00 55.79 A C ATOM 1589 O GLN A 211 54.839 25.720 −4.748 1.00 51.74 A O ATOM 1590 CB GLN A 211 54.761 23.112 −6.168 1.00 58.40 A C ATOM 1591 CG GLN A 211 54.940 22.113 −7.308 1.00 60.83 A C ATOM 1592 CD GLN A 211 55.915 20.988 −6.973 1.00 64.24 A C ATOM 1593 OE1 GLN A 211 56.594 20.463 −7.863 1.00 64.43 A O ATOM 1594 NE2 GLN A 211 55.983 20.614 −5.694 1.00 66.64 A N ATOM 1595 N ASP A 212 52.628 25.626 −5.048 1.00 54.01 A N ATOM 1596 CA ASP A 212 52.407 26.569 −3.959 1.00 56.91 A C ATOM 1597 C ASP A 212 52.447 25.914 −2.575 1.00 57.30 A C ATOM 1598 O ASP A 212 52.369 24.693 −2.454 1.00 55.10 A O ATOM 1599 CB ASP A 212 51.157 27.428 −4.209 1.00 56.98 A C ATOM 1600 CG ASP A 212 49.890 26.788 −3.737 1.00 57.67 A C ATOM 1601 OD1 ASP A 212 49.566 25.680 −4.212 1.00 57.46 A O ATOM 1602 OD2 ASP A 212 49.139 27.347 −2.909 1.00 59.70 A O ATOM 1603 N LEU A 213 52.623 26.738 −1.545 1.00 58.77 A N ATOM 1604 CA LEU A 213 52.860 26.263 −0.176 1.00 60.89 A C ATOM 1605 C LEU A 213 51.546 26.024 0.566 1.00 61.05 A C ATOM 1606 O LEU A 213 51.518 25.356 1.596 1.00 58.81 A O ATOM 1607 CB LEU A 213 53.725 27.270 0.598 1.00 61.26 A C ATOM 1608 CG LEU A 213 55.223 27.312 0.263 1.00 62.51 A C ATOM 1609 CD1 LEU A 213 55.490 27.170 −1.234 1.00 62.99 A C ATOM 1610 CD2 LEU A 213 55.857 28.602 0.793 1.00 63.51 A C ATOM 1611 N LYS A 214 50.470 26.602 0.039 1.00 62.93 A N ATOM 1612 CA LYS A 214 49.107 26.273 0.441 1.00 65.41 A C ATOM 1613 C LYS A 214 48.812 26.553 1.915 1.00 64.81 A C ATOM 1614 O LYS A 214 47.985 25.872 2.523 1.00 66.72 A O ATOM 1615 CB LYS A 214 48.781 24.808 0.083 1.00 66.77 A C ATOM 1616 CG LYS A 214 47.364 24.625 −0.469 1.00 69.56 A C ATOM 1617 CD LYS A 214 46.931 23.158 −0.553 1.00 70.85 A C ATOM 1618 CE LYS A 214 45.423 23.023 −0.346 1.00 70.83 A C ATOM 1619 NZ LYS A 214 44.873 21.747 −0.879 1.00 72.20 A N ATOM 1620 N MET A 215 49.465 27.568 2.480 1.00 62.76 A N ATOM 1621 CA MET A 215 49.187 27.959 3.862 1.00 61.10 A C ATOM 1622 C MET A 215 48.402 29.267 3.925 1.00 57.64 A C ATOM 1623 O MET A 215 48.495 30.102 3.024 1.00 57.95 A O ATOM 1624 CB MET A 215 50.474 28.035 4.701 1.00 62.37 A C ATOM 1625 CG MET A 215 51.555 28.957 4.190 1.00 63.11 A C ATOM 1626 SD MET A 215 53.067 28.833 5.203 1.00 62.67 A S ATOM 1627 CE MET A 215 54.211 28.376 3.978 1.00 62.72 A C ATOM 1628 N ASP A 216 47.599 29.420 4.976 1.00 53.34 A N ATOM 1629 CA ASP A 216 46.873 30.660 5.220 1.00 52.79 A C ATOM 1630 C ASP A 216 47.755 31.819 4.770 1.00 51.45 A C ATOM 1631 O ASP A 216 48.861 32.008 5.283 1.00 45.58 A O ATOM 1632 CB ASP A 216 46.517 30.792 6.705 1.00 53.42 A C ATOM 1633 CG ASP A 216 45.523 31.911 6.981 1.00 55.05 A C ATOM 1634 OD1 ASP A 216 45.109 32.639 6.045 1.00 53.37 A O ATOM 1635 OD2 ASP A 216 45.096 32.134 8.132 1.00 59.33 A O ATOM 1636 N CYS A 217 47.285 32.567 3.779 1.00 49.19 A N ATOM 1637 CA CYS A 217 48.119 33.601 3.172 1.00 49.39 A C ATOM 1638 C CYS A 217 48.345 34.770 4.144 1.00 48.78 A C ATOM 1639 O CYS A 217 49.274 35.554 3.966 1.00 49.38 A O ATOM 1640 CB CYS A 217 47.515 34.072 1.843 1.00 46.23 A C ATOM 1641 SG CYS A 217 45.917 34.862 2.016 1.00 48.31 A S ATOM 1642 N LYS A 218 47.489 34.869 5.166 1.00 48.17 A N ATOM 1643 CA LYS A 218 47.671 35.792 6.291 1.00 46.87 A C ATOM 1644 C LYS A 218 49.055 35.646 6.937 1.00 44.90 A C ATOM 1645 O LYS A 218 49.632 36.624 7.446 1.00 37.36 A O ATOM 1646 CB LYS A 218 46.585 35.551 7.345 1.00 48.51 A C ATOM 1647 CG LYS A 218 46.222 36.772 8.167 1.00 52.96 A C ATOM 1648 CD LYS A 218 44.760 36.731 8.616 1.00 54.70 A C ATOM 1649 CE LYS A 218 44.287 38.081 9.134 1.00 56.36 A C ATOM 1650 NZ LYS A 218 42.812 38.224 8.965 1.00 58.19 A N ATOM 1651 N GLU A 219 49.579 34.425 6.899 1.00 41.30 A N ATOM 1652 CA GLU A 219 50.894 34.118 7.460 1.00 41.57 A C ATOM 1653 C GLU A 219 52.043 34.739 6.674 1.00 41.40 A C ATOM 1654 O GLU A 219 53.112 35.003 7.245 1.00 38.39 A O ATOM 1655 CB GLU A 219 51.129 32.603 7.526 1.00 42.52 A C ATOM 1656 CG GLU A 219 50.072 31.806 8.284 1.00 43.99 A C ATOM 1657 CD GLU A 219 50.103 32.015 9.793 1.00 49.15 A C ATOM 1658 OE1 GLU A 219 49.422 31.235 10.503 1.00 49.54 A O ATOM 1659 OE2 GLU A 219 50.786 32.950 10.276 1.00 47.89 A O ATOM 1660 N TYR A 220 51.851 34.902 5.364 1.00 35.85 A N ATOM 1661 CA TYR A 220 52.867 35.487 4.479 1.00 35.18 A C ATOM 1662 C TYR A 220 53.164 36.913 4.830 1.00 28.13 A C ATOM 1663 O TYR A 220 54.185 37.465 4.445 1.00 34.25 A O ATOM 1664 CB TYR A 220 52.413 35.452 3.004 1.00 36.98 A C ATOM 1665 CG TYR A 220 52.256 34.069 2.389 1.00 37.36 A C ATOM 1666 CD1 TYR A 220 51.233 33.809 1.478 1.00 37.78 A C ATOM 1667 CD2 TYR A 220 53.132 33.026 2.702 1.00 40.58 A C ATOM 1668 CE1 TYR A 220 51.093 32.557 0.894 1.00 38.43 A C ATOM 1669 CE2 TYR A 220 52.996 31.775 2.136 1.00 40.55 A C ATOM 1670 CZ TYR A 220 51.962 31.539 1.233 1.00 41.11 A C ATOM 1671 OH TYR A 220 51.819 30.299 0.656 1.00 42.27 A O ATOM 1672 N ASN A 221 52.230 37.542 5.520 1.00 33.23 A N ATOM 1673 CA ASN A 221 52.322 38.933 5.865 1.00 35.09 A C ATOM 1674 C ASN A 221 52.201 39.102 7.363 1.00 31.87 A C ATOM 1675 O ASN A 221 51.682 40.126 7.831 1.00 33.51 A O ATOM 1676 CB ASN A 221 51.201 39.649 5.143 1.00 36.43 A C ATOM 1677 CG ASN A 221 51.102 39.213 3.695 1.00 37.85 A C ATOM 1678 OD1 ASN A 221 50.157 38.521 3.300 1.00 33.97 A O ATOM 1679 ND2 ASN A 221 52.119 39.561 2.910 1.00 28.28 A N ATOM 1680 N TYR A 222 52.668 38.088 8.091 1.00 39.46 A N ATOM 1681 CA TYR A 222 52.401 37.971 9.525 1.00 42.38 A C ATOM 1682 C TYR A 222 53.237 39.004 10.244 1.00 43.57 A C ATOM 1683 O TYR A 222 54.475 38.894 10.348 1.00 33.19 A O ATOM 1684 CB TYR A 222 52.673 36.559 10.071 1.00 45.87 A C ATOM 1685 CG TYR A 222 52.591 36.428 11.592 1.00 48.19 A C ATOM 1686 CD1 TYR A 222 51.870 37.337 12.382 1.00 51.26 A C ATOM 1687 CD2 TYR A 222 53.241 35.392 12.236 1.00 51.18 A C ATOM 1688 CE1 TYR A 222 51.815 37.204 13.774 1.00 52.32 A C ATOM 1689 CE2 TYR A 222 53.192 35.245 13.616 1.00 52.66 A C ATOM 1690 CZ TYR A 222 52.481 36.154 14.381 1.00 54.09 A C ATOM 1691 OH TYR A 222 52.436 36.004 15.751 1.00 56.15 A O ATOM 1692 N ASP A 223 52.486 39.968 10.768 1.00 46.73 A N ATOM 1693 CA ASP A 223 52.934 41.294 11.099 1.00 47.06 A C ATOM 1694 C ASP A 223 52.865 42.194 9.864 1.00 43.47 A C ATOM 1695 O ASP A 223 52.008 43.088 9.777 1.00 45.70 A O ATOM 1696 CB ASP A 223 54.339 41.289 11.693 1.00 50.64 A C ATOM 1697 CG ASP A 223 54.663 42.585 12.348 1.00 48.82 A C ATOM 1698 OD1 ASP A 223 54.041 42.879 13.392 1.00 56.19 A O ATOM 1699 OD2 ASP A 223 55.483 43.386 11.871 1.00 54.79 A O ATOM 1700 N LYS A 224 53.745 41.920 8.908 1.00 43.90 A N ATOM 1701 CA LYS A 224 54.128 42.889 7.872 1.00 43.50 A C ATOM 1702 C LYS A 224 54.720 42.221 6.651 1.00 38.65 A C ATOM 1703 O LYS A 224 55.321 41.177 6.749 1.00 37.31 A O ATOM 1704 CB LYS A 224 55.234 43.791 8.425 1.00 44.84 A C ATOM 1705 CG LYS A 224 54.814 45.182 8.824 1.00 49.52 A C ATOM 1706 CD LYS A 224 56.030 46.109 8.874 1.00 50.93 A C ATOM 1707 CE LYS A 224 56.970 45.783 10.029 1.00 52.43 A C ATOM 1708 NZ LYS A 224 58.303 45.329 9.550 1.00 53.74 A N ATOM 1709 N SER A 225 54.605 42.855 5.487 1.00 34.67 A N ATOM 1710 CA SER A 225 55.428 42.463 4.347 1.00 29.36 A C ATOM 1711 C SER A 225 55.923 43.766 3.727 1.00 23.18 A C ATOM 1712 O SER A 225 55.109 44.637 3.491 1.00 24.20 A O ATOM 1713 CB SER A 225 54.634 41.642 3.319 1.00 33.54 A C ATOM 1714 OG SER A 225 54.443 40.303 3.737 1.00 31.33 A O ATOM 1715 N ILE A 226 57.235 43.914 3.514 1.00 24.65 A N ATOM 1716 CA ILE A 226 57.814 45.209 3.080 1.00 24.70 A C ATOM 1717 C ILE A 226 58.879 45.132 1.973 1.00 20.50 A C ATOM 1718 O ILE A 226 59.568 44.138 1.762 1.00 22.18 A O ATOM 1719 CB ILE A 226 58.378 46.052 4.318 1.00 26.96 A C ATOM 1720 CG1 ILE A 226 59.715 45.495 4.804 1.00 29.94 A C ATOM 1721 CG2 ILE A 226 57.350 46.153 5.417 1.00 29.80 A C ATOM 1722 CD1 ILE A 226 60.392 46.347 5.918 1.00 30.64 A C ATOM 1723 N VAL A 227 59.046 46.229 1.249 1.00 21.76 A N ATOM 1724 CA VAL A 227 60.073 46.314 0.221 1.00 20.70 A C ATOM 1725 C VAL A 227 61.187 47.177 0.820 1.00 22.68 A C ATOM 1726 O VAL A 227 60.949 48.339 1.114 1.00 25.66 A O ATOM 1727 CB VAL A 227 59.486 46.982 −1.036 1.00 22.09 A C ATOM 1728 CG1 VAL A 227 60.466 46.919 −2.217 1.00 22.41 A C ATOM 1729 CG2 VAL A 227 58.172 46.322 −1.385 1.00 22.10 A C ATOM 1730 N ASP A 228 62.377 46.598 1.025 1.00 25.94 A N ATOM 1731 CA ASP A 228 63.488 47.250 1.750 1.00 26.69 A C ATOM 1732 C ASP A 228 64.859 47.181 1.053 1.00 25.68 A C ATOM 1733 O ASP A 228 65.552 46.160 1.089 1.00 28.14 A O ATOM 1734 CB ASP A 228 63.610 46.628 3.151 1.00 30.80 A C ATOM 1735 CG ASP A 228 64.507 47.435 4.073 1.00 36.12 A C ATOM 1736 OD1 ASP A 228 65.240 48.316 3.575 1.00 32.68 A O ATOM 1737 OD2 ASP A 228 64.544 47.261 5.315 1.00 43.13 A O ATOM 1738 N SER A 229 65.273 48.283 0.448 1.00 20.40 A N ATOM 1739 CA SER A 229 66.534 48.352 0.261 1.00 19.83 A C ATOM 1740 C SER A 229 67.766 48.269 0.668 1.00 20.00 A C ATOM 1741 O SER A 229 68.848 47.998 0.202 1.00 20.19 A O ATOM 1742 CB SER A 229 66.608 49.641 −1.084 1.00 19.70 A C ATOM 1743 OG SER A 229 66.651 50.793 −0.239 1.00 20.04 A O ATOM 1744 N GLY A 230 67.582 48.539 1.955 1.00 24.02 A N ATOM 1745 CA GLY A 230 68.666 48.429 2.928 1.00 30.23 A C ATOM 1746 C GLY A 230 69.016 46.983 3.270 1.00 32.91 A C ATOM 1747 O GLY A 230 70.179 46.641 3.517 1.00 37.27 A O ATOM 1748 N THR A 231 67.998 46.129 3.290 1.00 35.70 A N ATOM 1749 CA THR A 231 68.157 44.736 3.700 1.00 36.19 A C ATOM 1750 C THR A 231 68.647 43.943 2.502 1.00 36.17 A C ATOM 1751 O THR A 231 68.125 44.098 1.392 1.00 36.88 A O ATOM 1752 CB THR A 231 66.811 44.203 4.216 1.00 36.06 A C ATOM 1753 OG1 THR A 231 66.371 44.988 5.333 1.00 41.33 A O ATOM 1754 CG2 THR A 231 66.931 42.806 4.770 1.00 39.41 A C ATOM 1755 N THR A 232 69.676 43.117 2.701 1.00 34.96 A N ATOM 1756 CA THR A 232 70.213 42.299 1.624 1.00 31.73 A C ATOM 1757 C THR A 232 69.299 41.111 1.311 1.00 35.19 A C ATOM 1758 O THR A 232 69.149 40.754 0.150 1.00 34.98 A O ATOM 1759 CB THR A 232 71.612 41.737 1.968 1.00 36.41 A C ATOM 1760 OG1 THR A 232 72.502 42.796 2.338 1.00 33.05 A O ATOM 1761 CG2 THR A 232 72.274 41.136 0.735 1.00 36.22 A C ATOM 1762 N ASN A 233 68.735 40.502 2.352 1.00 38.19 A N ATOM 1763 CA ASN A 233 68.029 39.230 2.211 1.00 41.17 A C ATOM 1764 C ASN A 233 66.520 39.365 2.052 1.00 40.23 A C ATOM 1765 O ASN A 233 65.922 40.416 2.327 1.00 39.76 A O ATOM 1766 CB ASN A 233 68.307 38.323 3.420 1.00 43.40 A C ATOM 1767 CG ASN A 233 69.767 37.864 3.503 1.00 44.47 A C ATOM 1768 OD1 ASN A 233 70.293 37.678 4.593 1.00 53.39 A O ATOM 1769 ND2 ASN A 233 70.409 37.667 2.360 1.00 47.21 A N ATOM 1770 N LEU A 234 65.927 38.259 1.613 1.00 39.45 A N ATOM 1771 CA LEU A 234 64.497 38.025 1.667 1.00 35.83 A C ATOM 1772 C LEU A 234 64.178 37.466 3.035 1.00 31.21 A C ATOM 1773 O LEU A 234 64.504 36.342 3.319 1.00 35.53 A O ATOM 1774 CB LEU A 234 64.119 37.022 0.562 1.00 41.31 A C ATOM 1775 CG LEU A 234 62.727 36.992 −0.082 1.00 42.04 A C ATOM 1776 CD1 LEU A 234 62.447 35.596 −0.613 1.00 45.40 A C ATOM 1777 CD2 LEU A 234 61.630 37.429 0.851 1.00 42.45 A C ATOM 1778 N ARG A 235 63.564 38.263 3.906 1.00 39.51 A N ATOM 1779 CA ARG A 235 63.200 37.811 5.254 1.00 37.00 A C ATOM 1780 C ARG A 235 61.737 37.315 5.290 1.00 38.00 A C ATOM 1781 O ARG A 235 60.863 37.918 4.699 1.00 31.41 A O ATOM 1782 CB ARG A 235 63.434 38.930 6.278 1.00 40.50 A C ATOM 1783 CG ARG A 235 64.843 39.557 6.210 1.00 43.67 A C ATOM 1784 CD ARG A 235 65.208 40.478 7.378 1.00 46.74 A C ATOM 1785 NE ARG A 235 65.177 39.774 8.659 1.00 49.76 A N ATOM 1786 CZ ARG A 235 64.729 40.272 9.823 1.00 52.94 A C ATOM 1787 NH1 ARG A 235 64.272 41.522 9.918 1.00 51.18 A N ATOM 1788 NH2 ARG A 235 64.743 39.503 10.914 1.00 51.36 A N ATOM 1789 N LEU A 236 61.473 36.226 6.008 1.00 37.36 A N ATOM 1790 CA LEU A 236 60.156 35.571 5.992 1.00 37.98 A C ATOM 1791 C LEU A 236 59.691 35.254 7.408 1.00 39.27 A C ATOM 1792 O LEU A 236 60.503 34.847 8.230 1.00 37.29 A O ATOM 1793 CB LEU A 236 60.238 34.271 5.210 1.00 37.66 A C ATOM 1794 CG LEU A 236 60.689 34.363 3.745 1.00 36.72 A C ATOM 1795 CD1 LEU A 236 60.713 32.994 3.135 1.00 34.34 A C ATOM 1796 CD2 LEU A 236 59.784 35.269 2.922 1.00 37.91 A C ATOM 1797 N PRO A 237 58.399 35.408 7.719 1.00 37.12 A N ATOM 1798 CA PRO A 237 57.939 35.039 9.061 1.00 35.72 A C ATOM 1799 C PRO A 237 58.324 33.600 9.304 1.00 36.04 A C ATOM 1800 O PRO A 237 58.364 32.870 8.326 1.00 31.43 A O ATOM 1801 CB PRO A 237 56.425 35.222 8.985 1.00 36.23 A C ATOM 1802 CG PRO A 237 56.243 36.263 7.917 1.00 36.72 A C ATOM 1803 CD PRO A 237 57.297 35.918 6.887 1.00 37.44 A C ATOM 1804 N LYS A 238 58.647 33.213 10.538 1.00 34.49 A N ATOM 1805 CA LYS A 238 59.098 31.839 10.805 1.00 34.56 A C ATOM 1806 C LYS A 238 58.322 30.780 10.051 1.00 32.78 A C ATOM 1807 O LYS A 238 58.908 29.860 9.452 1.00 32.03 A O ATOM 1808 CB LYS A 238 58.881 31.433 12.243 1.09 34.24 A C ATOM 1809 CG LYS A 238 59.299 32.363 13.281 1.00 30.75 A C ATOM 1810 CD LYS A 238 58.868 31.768 14.539 1.00 5.80 A C ATOM 1811 CE LYS A 238 57.493 31.846 14.975 1.00 27.32 A C ATOM 1812 NZ LYS A 238 57.007 31.123 16.239 1.00 32.55 A N ATOM 1813 N LYS A 239 56.998 30.879 10.142 1.00 28.36 A N ATOM 1814 CA LYS A 239 56.149 29.747 9.735 1.00 37.49 A C ATOM 1815 C LYS A 239 56.292 29.508 8.233 1.00 35.49 A C ATOM 1816 O LYS A 239 56.310 28.360 7.762 1.00 30.89 A O ATOM 1817 CB LYS A 239 54.675 29.990 10.108 1.00 39.29 A C ATOM 1818 CG LYS A 239 54.110 28.997 11.108 1.00 46.03 A C ATOM 1819 CD LYS A 239 52.700 29.406 11.566 1.00 48.69 A C ATOM 1820 CE LYS A 239 51.634 28.404 11.117 1.00 50.81 A C ATOM 1821 NZ LYS A 239 50.243 28.846 11.463 1.00 49.91 A N ATOM 1822 N VAL A 240 56.411 30.614 7.497 1.00 32.65 A N ATOM 1823 CA VAL A 240 56.599 30.569 6.057 1.00 32.95 A C ATOM 1824 C VAL A 240 58.018 30.172 5.684 1.00 28.03 A C ATOM 1825 O VAL A 240 58.201 29.484 4.704 1.00 26.73 A O ATOM 1826 CB VAL A 240 56.323 31.928 5.390 1.00 28.86 A C ATOM 1827 CG1 VAL A 240 56.411 31.801 3.908 1.00 29.02 A C ATOM 1828 CG2 VAL A 240 54.963 32.517 5.818 1.00 33.40 A C ATOM 1829 N PHE A 241 59.019 30.655 6.430 1.00 31.69 A N ATOM 1830 CA PHE A 241 60.402 30.267 6.159 1.00 34.11 A C ATOM 1831 C PHE A 241 60.559 28.745 6.338 1.00 32.98 A C ATOM 1832 O PHE A 241 61.100 28.029 5.470 1.00 29.40 A O ATOM 1833 CB PHE A 241 61.360 30.997 7.095 1.00 35.69 A C ATOM 1834 CG PHE A 241 62.748 30.459 7.057 1.00 39.37 A C ATOM 1835 CD1 PHE A 241 63.601 30.785 6.012 1.00 42.58 A C ATOM 1836 CD2 PHE A 241 63.197 29.583 8.047 1.00 42.39 A C ATOM 1837 CE1 PHE A 241 64.895 30.272 5.968 1.00 43.06 A C ATOM 1838 CE2 PHE A 241 64.479 29.073 8.007 1.00 38.87 A C ATOM 1839 CZ PHE A 241 65.329 29.419 6.964 1.00 43.23 A C ATOM 1840 N GLU A 242 60.075 28.249 7.468 1.00 32.78 A N ATOM 1841 CA GLU A 242 60.011 26.800 7.696 1.00 36.60 A C ATOM 1842 C GLU A 242 59.505 26.025 6.487 1.00 33.79 A C ATOM 1843 O GLU A 242 60.160 25.083 6.053 1.00 35.48 A O ATOM 1844 CB GLU A 242 59.123 26.473 8.899 1.00 37.43 A C ATOM 1845 CG GLU A 242 59.830 26.686 10.217 1.00 43.87 A C ATOM 1846 CD GLU A 242 60.878 25.635 10.508 1.00 45.01 A C ATOM 1847 OE1 GLU A 242 61.759 25.906 11.358 1.00 45.07 A O ATOM 1848 OE2 GLU A 242 60.818 24.545 9.888 1.00 52.08 A O ATOM 1849 N ALA A 243 58.358 26.437 5.942 1.00 34.61 A N ATOM 1850 CA ALA A 243 57.752 25.723 4.804 1.00 36.67 A C ATOM 1851 C ALA A 243 58.531 25.984 3.523 1.00 35.54 A C ATOM 1852 O ALA A 243 58.735 25.093 2.706 1.00 30.69 A O ATOM 1853 CB ALA A 243 56.307 26.138 4.615 1.00 36.74 A C ATOM 1854 N ALA A 244 58.961 27.231 3.375 1.00 36.29 A N ATOM 1855 CA ALA A 244 59.717 27.682 2.224 1.00 36.28 A C ATOM 1856 C ALA A 244 60.970 26.841 2.063 1.00 36.59 A C ATOM 1857 O ALA A 244 61.133 26.184 1.058 1.00 35.35 A O ATOM 1858 CB ALA A 244 60.073 29.142 2.383 1.00 34.54 A C ATOM 1859 N VAL A 245 61.853 26.884 3.064 1.00 38.90 A N ATOM 1860 CA VAL A 245 63.002 25.982 3.143 1.00 42.56 A C ATOM 1861 C VAL A 245 62.658 24.500 2.899 1.00 40.13 A C ATOM 1862 O VAL A 245 63.341 23.835 2.114 1.00 40.38 A O ATOM 1863 CB VAL A 245 63.742 26.130 4.515 1.00 43.37 A C ATOM 1864 CG1 VAL A 245 64.651 24.918 4.821 1.09 47.23 A C ATOM 1865 CG2 VAL A 245 64.541 27.420 4.534 1.00 44.13 A C ATOM 1866 N LYS A 246 61.627 23.974 3.556 1.00 39.54 A N ATOM 1867 CA LYS A 246 61.270 22.556 3.352 1.00 44.44 A C ATOM 1868 C LYS A 246 61.172 22.215 1.859 1.00 43.12 A C ATOM 1869 O LYS A 246 61.745 21.233 1.407 1.00 40.51 A O ATOM 1870 CB LYS A 246 59.965 22.180 4.068 1.00 46.80 A C ATOM 1871 CG LYS A 246 59.575 20.695 3.924 1.00 50.38 A C ATOM 1872 CD LYS A 246 58.263 20.380 4.653 1.00 52.29 A C ATOM 1873 CE LYS A 246 57.530 19.182 4.042 1.00 54.52 A C ATOM 1874 NZ LYS A 246 58.452 18.072 3.656 1.00 53.80 A N ATOM 1875 N SER A 247 60.473 23.051 1.097 1.00 44.68 A N ATOM 1876 CA SER A 247 60.282 22.809 −0.337 1.00 45.24 A C ATOM 1877 C SER A 247 61.505 23.062 −1.226 1.00 43.18 A C ATOM 1878 O SER A 247 61.653 22.423 −2.258 1.00 38.59 A O ATOM 1879 CB SER A 247 59.126 23.654 −0.869 1.00 45.97 A C ATOM 1880 OG SER A 247 59.035 23.478 −2.266 1.00 42.87 A O ATOM 1881 N ILE A 248 62.345 24.027 −0.861 1.00 47.83 A N ATOM 1882 CA ILE A 248 63.534 24.348 −1.658 1.00 50.81 A C ATOM 1883 C ILE A 248 64.570 23.241 −1.475 1.00 52.35 A C ATOM 1884 O ILE A 248 65.200 22.787 −2.440 1.00 48.20 A O ATOM 1885 CB ILE A 248 64.116 25.716 −1.260 1.00 51.35 A C ATOM 1886 CG1 ILE A 248 63.101 26.823 −1.548 1.00 50.95 A C ATOM 1887 CG2 ILE A 248 65.428 25.983 −2.015 1.00 51.10 A C ATOM 1888 CD1 ILE A 248 63.447 28.154 −0.913 1.00 51.52 A C ATOM 1889 N LYS A 249 64.725 22.814 −0.227 1.00 53.72 A N ATOM 1890 CA LYS A 249 65.451 21.585 0.108 1.00 59.31 A C ATOM 1891 C LYS A 249 65.021 20.377 −0.745 1.00 61.00 A C ATOM 1892 O LYS A 249 65.871 19.634 −1.233 1.00 58.84 A O ATOM 1893 CB LYS A 249 65.260 21.257 1.598 1.00 61.17 A C ATOM 1894 CG LYS A 249 66.419 20.522 2.240 1.00 63.43 A C ATOM 1895 CD LYS A 249 66.187 20.317 3.740 1.00 65.86 A C ATOM 1896 CE LYS A 249 66.299 21.620 4.530 1.00 67.19 A C ATOM 1897 NZ LYS A 249 66.791 21.417 5.929 1.00 68.30 A N ATOM 1898 N ALA A 250 63.711 20.207 −0.942 1.00 63.51 A N ATOM 1899 CA ALA A 250 63.160 19.006 −1.589 1.00 66.01 A C ATOM 1900 C ALA A 250 63.564 18.839 −3.059 1.00 67.43 A C ATOM 1901 O ALA A 250 64.214 17.861 −3.408 1.00 67.59 A O ATOM 1902 CB ALA A 250 61.635 18.974 −1.455 1.00 65.47 A C ATOM 1903 N ALA A 251 63.185 19.783 −3.917 1.00 69.93 A N ATOM 1904 CA ALA A 251 63.539 19.694 −5.342 1.00 70.60 A C ATOM 1905 C ALA A 251 64.985 20.123 −5.633 1.00 70.50 A C ATOM 1906 O ALA A 251 65.364 20.268 −6.794 1.00 69.29 A O ATOM 1907 CB ALA A 251 62.547 20.488 −6.212 1.00 70.96 A C ATOM 1908 N SER A 252 65.778 20.338 −4.582 1.00 70.95 A N ATOM 1909 CA SER A 252 67.213 20.562 −4.718 1.00 72.23 A C ATOM 1910 C SER A 252 68.016 19.483 −3.985 1.00 73.46 A C ATOM 1911 O SER A 252 69.189 19.680 −3.661 1.00 71.37 A O ATOM 1912 CB SER A 252 67.582 21.951 −4.189 1.00 72.68 A C ATOM 1913 OG SER A 252 67.505 21.999 −2.775 1.00 73.18 A O ATOM 1914 N SER A 253 67.389 18.332 −3.756 1.00 75.44 A N ATOM 1915 CA SER A 253 68.011 17.239 −3.011 1.00 77.44 A C ATOM 1916 C SER A 253 69.079 16.491 −3.819 1.00 79.67 A C ATOM 1917 O SER A 253 69.783 15.645 −3.263 1.00 79.72 A O ATOM 1918 CB SER A 253 66.944 16.250 −2.532 1.00 77.46 A C ATOM 1919 OG SER A 253 66.037 16.870 −1.637 1.00 76.30 A O ATOM 1920 N THR A 254 69.196 16.799 −5.116 1.00 81.88 A N ATOM 1921 CA THR A 254 70.232 16.215 −5.983 1.00 83.80 A C ATOM 1922 C THR A 254 71.624 16.245 −5.334 1.00 85.34 A C ATOM 1923 O THR A 254 72.423 15.330 −5.538 1.00 85.86 A O ATOM 1924 CB THR A 254 70.270 16.936 −7.360 1.00 83.52 A C ATOM 1925 OG1 THR A 254 68.992 16.851 −7.999 1.00 83.21 A O ATOM 1926 CG2 THR A 254 71.205 16.228 −8.342 1.00 83.62 A C ATOM 1927 N GLU A 255 71.909 17.296 −4.565 1.00 86.72 A N ATOM 1928 CA GLU A 255 73.121 17.354 −3.746 1.00 87.75 A C ATOM 1929 C GLU A 255 72.785 17.714 −2.302 1.00 88.51 A C ATOM 1930 O GLU A 255 72.017 18.643 −2.048 1.00 89.05 A O ATOM 1931 CB GLU A 255 74.103 18.379 −4.307 1.00 87.94 A C ATOM 1932 CG GLU A 255 74.553 18.101 −5.731 1.00 88.21 A C ATOM 1933 CD GLU A 255 75.403 19.222 −6.297 1.00 88.85 A C ATOM 1934 OE1 GLU A 255 76.162 19.847 −5.521 1.00 88.18 A O ATOM 1935 OE2 GLU A 255 75.308 19.478 −7.518 1.00 89.16 A O ATOM 1936 N LYS A 256 73.367 16.973 −1.361 1.00 89.37 A N ATOM 1937 CA LYS A 256 73.181 17.233 0.066 1.00 89.70 A C ATOM 1938 C LYS A 256 74.060 18.406 0.515 1.00 89.43 A C ATOM 1939 O LYS A 256 75.211 18.519 0.090 1.00 90.96 A O ATOM 1940 CB LYS A 256 73.524 15.976 0.878 1.00 89.79 A C ATOM 1941 CG LYS A 256 73.344 16.118 2.390 1.00 89.80 A C ATOM 1942 CD LYS A 256 73.488 14.778 3.106 1.00 89.76 A C ATOM 1943 CE LYS A 256 74.916 14.250 3.037 1.00 89.66 A C ATOM 1944 NZ LYS A 256 75.135 13.099 3.955 1.00 89.59 A N ATOM 1945 N PHE A 257 73.509 19.278 1.359 1.00 88.33 A N ATOM 1946 CA PHE A 257 74.277 20.358 1.988 1.00 87.80 A C ATOM 1947 C PHE A 257 73.957 20.434 3.486 1.00 85.90 A C ATOM 1948 O PHE A 257 72.901 19.963 3.916 1.00 84.62 A O ATOM 1949 CB PHE A 257 73.977 21.698 1.307 1.00 88.75 A C ATOM 1950 CG PHE A 257 74.158 21.672 −0.188 1.00 90.18 A C ATOM 1951 CD1 PHE A 257 73.128 22.071 −1.035 1.00 90.73 A C ATOM 1952 CD2 PHE A 257 75.358 21.243 −0.747 1.00 90.65 A C ATOM 1953 CE1 PHE A 257 73.295 22.043 −2.417 1.00 91.50 A C ATOM 1954 CE2 PHE A 257 75.530 21.208 −2.125 1.00 91.35 A C ATOM 1955 CZ PHE A 257 74.499 21.611 −2.961 1.00 91.69 A C ATOM 1956 N PRO A 258 74.857 21.019 4.282 1.00 84.41 A N ATOM 1957 CA PRO A 258 74.671 21.079 5.743 1.00 83.94 A C ATOM 1958 C PRO A 258 73.334 21.697 6.182 1.00 83.10 A C ATOM 1959 O PRO A 258 72.764 22.519 5.459 1.00 82.64 A O ATOM 1960 CB PRO A 258 75.840 21.957 6.218 1.00 83.97 A C ATOM 1961 CG PRO A 258 76.862 21.878 5.141 1.00 84.54 A C ATOM 1962 CD PRO A 258 76.116 21.664 3.861 1.00 84.44 A C ATOM 1963 N ASP A 259 72.852 21.302 7.360 1.00 81.28 A N ATOM 1964 CA ASP A 259 71.608 21.847 7.916 1.00 79.36 A C ATOM 1965 C ASP A 259 71.767 23.327 8.300 1.00 76.80 A C ATOM 1966 O ASP A 259 70.804 24.097 8.228 1.00 75.77 A O ATOM 1967 CB ASP A 259 71.140 21.025 9.133 1.00 80.43 A C ATOM 1968 CG ASP A 259 69.749 20.420 8.947 1.00 81.62 A C ATOM 1969 OD1 ASP A 259 69.433 19.944 7.832 1.00 81.91 A O ATOM 1970 OD2 ASP A 259 68.906 20.364 9.870 1.00 82.81 A O ATOM 1971 N GLY A 260 72.981 23.716 8.694 1.00 72.15 A N ATOM 1972 CA GLY A 260 73.280 25.095 9.051 1.00 68.23 A C ATOM 1973 C GLY A 260 73.394 26.055 7.873 1.00 65.01 A C ATOM 1974 O GLY A 260 73.306 27.266 8.055 1.00 62.06 A O ATOM 1975 N PHE A 261 73.601 25.529 6.670 1.00 61.00 A N ATOM 1976 CA PHE A 261 73.582 26.350 5.456 1.00 59.12 A C ATOM 1977 C PHE A 261 72.247 27.101 5.311 1.00 57.30 A C ATOM 1978 O PHE A 261 72.217 28.296 5.013 1.00 47.15 A O ATOM 1979 CB PHE A 261 73.833 25.475 4.222 1.00 59.54 A C ATOM 1980 CG PHE A 261 73.504 26.148 2.920 1.00 58.56 A C ATOM 1981 CD1 PHE A 261 74.289 27.187 2.447 1.00 57.89 A C ATOM 1982 CD2 PHE A 261 72.415 25.741 2.169 1.00 58.88 A C ATOM 1983 CE1 PHE A 261 73.996 27.807 1.259 1.00 56.77 A C ATOM 1984 CE2 PHE A 261 72.118 26.359 0.972 1.00 58.83 A C ATOM 1985 CZ PHE A 261 72.912 27.393 0.516 1.00 58.32 A C ATOM 1986 N TRP A 262 71.151 26.389 5.557 1.00 56.79 A N ATOM 1987 CA TRP A 262 69.813 26.949 5.396 1.00 58.03 A C ATOM 1988 C TRP A 262 69.475 27.995 6.467 1.00 58.02 A C ATOM 1989 O TRP A 262 68.525 28.760 6.296 1.00 57.45 A O ATOM 1990 CB TRP A 262 68.759 25.832 5.406 1.00 59.10 A C ATOM 1991 CG TRP A 262 69.026 24.721 4.432 1.00 60.40 A C ATOM 1992 CD1 TRP A 262 69.372 23.430 4.730 1.00 61.96 A C ATOM 1993 CD2 TRP A 262 68.974 24.800 3.003 1.00 61.91 A C ATOM 1994 NE1 TRP A 262 69.535 22.704 3.574 1.00 60.97 A N ATOM 1995 CE2 TRP A 262 69.298 23.520 2.498 1.00 61.58 A C ATOM 1996 CE3 TRP A 262 68.688 25.824 2.092 1.00 62.89 A C ATOM 1997 CZ2 TRP A 262 69.343 23.240 1.132 1.00 62.27 A C ATOM 1998 CZ3 TRP A 262 68.729 25.543 0.731 1.00 63.90 A C ATOM 1999 CH2 TRP A 262 69.057 24.260 0.267 1.00 63.92 A C ATOM 2000 N LEU A 263 70.236 28.025 7.563 1.00 56.89 A N ATOM 2001 CA LEU A 263 70.040 29.026 8.626 1.00 57.55 A C ATOM 2002 C LEU A 263 71.038 30.204 8.576 1.00 55.97 A C ATOM 2003 O LEU A 263 71.084 31.020 9.501 1.00 51.83 A O ATOM 2004 CB LEU A 263 70.102 28.355 10.010 1.00 58.30 A C ATOM 2005 CG LEU A 263 68.913 27.494 10.470 1.00 61.17 A C ATOM 2006 CD1 LEU A 263 67.569 28.209 10.298 1.00 62.02 A C ATOM 2007 CD2 LEU A 263 68.900 26.160 9.759 1.00 61.49 A C ATOM 2008 N GLY A 264 71.821 30.300 7.501 1.00 54.23 A N ATOM 2009 CA GLY A 264 72.793 31.378 7.352 1.00 55.51 A C ATOM 2010 C GLY A 264 73.964 31.272 8.318 1.00 53.62 A C ATOM 2011 O GLY A 264 74.657 32.259 8.582 1.00 52.01 A O ATOM 2012 N GLU A 265 74.180 30.057 8.822 1.00 52.02 A N ATOM 2013 CA GLU A 265 75.202 29.749 9.818 1.00 52.34 A C ATOM 2014 C GLU A 265 76.498 29.185 9.216 1.00 51.88 A C ATOM 2015 O GLU A 265 77.521 29.092 9.902 1.00 50.86 A O ATOM 2016 CB GLU A 265 74.620 28.757 10.823 1.00 53.23 A C ATOM 2017 CG GLU A 265 73.484 29.351 11.651 1.00 56.42 A C ATOM 2018 CD GLU A 265 72.811 28.342 12.572 1.00 59.67 A C ATOM 2019 OE1 GLU A 265 73.053 27.121 12.415 1.00 62.41 A O ATOM 2020 OE2 GLU A 265 72.029 28.777 13.451 1.00 58.43 A O ATOM 2021 N GLN A 266 76.444 28.781 7.951 1.00 48.71 A N ATOM 2022 CA GLN A 266 77.650 28.438 7.197 1.00 50.93 A C ATOM 2023 C GLN A 266 77.436 28.743 5.726 1.00 50.91 A C ATOM 2024 O GLN A 266 76.300 28.790 5.262 1.00 48.81 A O ATOM 2025 CB GLN A 266 77.919 26.957 7.385 1.00 51.13 A C ATOM 2026 CG GLN A 266 79.152 26.489 6.603 0.00 20.00 A C ATOM 2027 CD GLN A 266 79.377 25.016 6.849 0.00 20.00 A C ATOM 2028 OE1 GLN A 266 79.286 24.174 5.970 0.00 20.00 A O ATOM 2029 NE2 GLN A 266 79.677 24.718 8.129 0.00 20.00 A N ATOM 2030 N LEU A 267 78.523 28.947 4.988 1.00 52.35 A N ATOM 2031 CA LEU A 267 78.414 29.197 3.555 1.00 55.74 A C ATOM 2032 C LEU A 267 78.794 27.955 2.759 1.00 55.94 A C ATOM 2033 O LEU A 267 79.623 27.161 3.189 1.00 55.10 A O ATOM 2034 CB LEU A 267 79.228 30.427 3.117 1.00 57.95 A C ATOM 2035 CG LEU A 267 80.592 30.763 3.719 1.00 59.40 A C ATOM 2036 CD1 LEU A 267 81.667 29.797 3.226 1.00 61.73 A C ATQM 2037 CD2 LEU A 267 80.966 32.199 3.379 1.00 59.25 A C ATOM 2038 N VAL A 268 78.141 27.778 1.614 1.00 59.08 A N ATOM 2039 CA VAL A 268 78.394 26.635 0.734 1.00 63.27 A C ATOM 2040 C VAL A 268 79.437 27.028 −0.317 1.00 65.28 A C ATOM 2041 O VAL A 268 79.581 28.206 −0.628 1.00 65.73 A O ATOM 2042 CB VAL A 268 77.072 26.103 0.084 1.00 63.60 A C ATOM 2043 CG1 VAL A 268 76.461 27.114 −0.900 1.00 64.14 A C ATOM 2044 CG2 VAL A 268 77.302 24.759 −0.593 1.00 63.65 A C ATOM 2045 N CYS A 269 80.182 26.050 −0.830 1.00 67.59 A N ATOM 2046 CA CYS A 269 81.255 26.315 −1.794 1.00 70.85 A C ATOM 2047 C CYS A 269 81.288 25.302 −2.943 1.00 71.91 A C ATOM 2048 O CYS A 269 81.068 24.106 −2.740 1.00 70.92 A O ATOM 2049 CB CYS A 269 82.618 26.330 −1.086 1.00 71.01 A C ATOM 2050 SG CYS A 269 82.804 27.634 0.160 1.00 73.46 A S ATOM 2051 N TRP A 270 81.560 25.804 −4.147 1.00 73.59 A N ATQM 2052 CA TRP A 270 81.768 24.975 −5.335 1.00 74.68 A C ATOM 2053 C TRP A 270 83.036 25.412 −6.065 1.00 75.66 A C ATOM 2054 O TRP A 270 83.455 26.563 −5.952 1.00 74.31 A O ATOM 2055 CB TRP A 270 80.584 25.108 −6.289 1.00 75.03 A C ATOM 2056 CG TRP A 270 79.330 24.451 −5.812 1.00 74.79 A C ATOM 2057 CD1 TRP A 270 79.034 23.118 −5.848 1.00 74.58 A C ATOM 2058 CD2 TRP A 270 78.191 25.099 −5.239 1.00 74.13 A C ATOM 2059 NE1 TRP A 270 77.781 22.898 −5.329 1.00 74.78 A N ATOM 2060 CE2 TRP A 270 77.241 24.098 −4.946 1.00 74.47 A C ATOM 2061 CE3 TRP A 270 77.875 26.431 −4.939 1.00 73.49 A C ATOM 2062 CZ2 TRP A 270 76.000 24.386 −4.372 1.00 74.22 A C ATOM 2063 CZ3 TRP A 270 76.649 26.715 −4.371 1.00 73.73 A C ATOM 2064 CH2 TRP A 270 75.727 25.696 −4.088 1.00 73.99 A C ATOM 2065 N GLN A 271 83.633 24.497 −6.827 1.00 77.31 A N ATOM 2066 CA GLN A 271 84.835 24.808 −7.603 1.00 78.64 A C ATOM 2067 C GLN A 271 84.559 25.956 −8.579 1.00 79.98 A C ATOM 2068 O GLN A 271 83.424 26.136 −9.025 1.00 79.95 A O ATOM 2069 CB GLN A 271 85.233 23.565 −8.378 1.00 78.38 A C ATOM 2070 CG GLN A 271 85.694 22.427 −7.461 0.00 20.00 A C ATOM 2071 CD GLN A 271 86.108 21.239 −8.297 0.00 20.00 A C ATOM 2072 OE1 GLN A 271 86.517 20.197 −7.812 0.00 20.00 A O ATOM 2073 NE2 GLN A 271 85.995 21.443 −9.624 0.00 20.00 A N ATOM 2074 N ALA A 272 85.596 26.733 −8.891 1.00 81.27 A N ATOM 2075 CA ALA A 272 85.467 27.927 −9.736 1.00 82.23 A C ATOM 2076 C ALA A 272 84.604 27.706 −10.989 1.00 82.74 A C ATOM 2077 O ALA A 272 85.006 27.012 −11.926 1.00 82.97 A O ATOM 2078 CB ALA A 272 86.850 28.443 −10.131 1.00 82.17 A C ATOM 2079 N GLY A 273 83.408 28.289 −10.977 1.00 83.80 A N ATOM 2080 CA GLY A 273 82.523 28.301 −12.132 1.00 84.66 A C ATOM 2081 C GLY A 273 81.761 27.008 −12.373 1.00 84.93 A C ATOM 2082 O GLY A 273 81.383 26.720 −13.511 1.00 86.15 A O ATOM 2083 N THR A 274 81.509 26.250 −11.305 1.00 84.63 A N ATOM 2084 CA THR A 274 80.861 24.940 −11.396 1.00 84.75 A C ATOM 2085 C THR A 274 79.570 24.921 −10.581 1.00 84.35 A C ATOM 2086 O THR A 274 79.158 23.880 −10.064 1.00 82.91 A O ATOM 2087 CB THR A 274 81.812 23.828 −10.895 1.00 85.61 A C ATOM 2088 OG1 THR A 274 82.135 24.043 −9.514 1.00 85.37 A O ATOM 2089 CG2 THR A 274 83.162 23.879 −11.618 1.00 86.24 A C ATOM 2090 N THR A 275 78.929 26.079 −10.480 1.00 84.51 A N ATOM 2091 CA THR A 275 77.719 26.213 −9.688 1.00 85.22 A C ATOM 2092 C THR A 275 76.535 25.616 −10.451 1.00 84.97 A C ATOM 2093 O THR A 275 76.311 25.959 −11.614 1.00 83.74 A O ATOM 2094 CB THR A 275 77.450 27.690 −9.370 1.00 85.63 A C ATOM 2095 OG1 THR A 275 78.649 28.313 −8.889 1.00 87.20 A O ATOM 2096 CG2 THR A 275 76.472 27.827 −8.210 1.00 86.40 A C ATOM 2097 N PRO A 276 75.790 24.718 −9.808 1.00 84.86 A N ATOM 2098 CA PRO A 276 74.591 24.138 −10.420 1.00 84.84 A C ATOM 2099 C PRO A 276 73.386 25.087 −10.330 1.00 84.60 A C ATOM 2100 O PRO A 276 72.759 25.213 −9.270 1.00 83.40 A O ATOM 2101 CB PRO A 276 74.363 22.864 −9.599 1.00 85.26 A C ATOM 2102 CG PRO A 276 74.945 23.160 −8.247 1.00 84.89 A C ATOM 2103 CD PRO A 276 76.033 24.178 −8.456 1.00 84.87 A C ATOM 2104 N TRP A 277 73.084 25.757 −11.441 1.00 83.87 A N ATOM 2105 CA TRP A 277 71.945 26.671 −11.512 1.00 82.59 A C ATOM 2106 C TRP A 277 70.645 25.914 −11.259 1.00 78.91 A C ATOM 2107 O TRP A 277 69.868 26.253 −10.361 1.00 76.37 A O ATOM 2108 CB TRP A 277 71.852 27.327 −12.903 1.00 84.62 A C ATOM 2109 CG TRP A 277 72.863 28.426 −13.258 1.00 86.23 A C ATOM 2110 CD1 TRP A 277 73.299 28.743 −14.520 1.00 86.71 A C ATOM 2111 CD2 TRP A 277 73.518 29.358 −12.371 1.00 86.55 A C ATOM 2112 NE1 TRP A 277 74.186 29.792 −14.473 1.00 86.87 A N ATOM 2113 CE2 TRP A 277 74.340 30.190 −13.171 1.00 87.19 A C ATOM 2114 CE3 TRP A 277 73.503 29.573 −10.982 1.00 86.48 A C ATOM 2115 CZ2 TRP A 277 75.129 31.211 −12.632 1.00 87.46 A C ATOM 2116 CZ3 TRP A 277 74.291 30.587 −10.449 1.00 86.65 A C ATOM 2117 CH2 TRP A 277 75.092 31.392 −11.273 1.00 87.15 A C ATOM 2118 N ASN A 278 70.450 24.864 −12.052 1.00 75.16 A N ATOM 2119 CA ASN A 278 69.149 24.232 −12.228 1.00 71.96 A C ATOM 2120 C ARN A 278 68.678 23.332 −11.094 1.00 68.53 A C ATOM 2121 O ASN A 278 67.516 22.952 −11.057 1.00 65.41 A O ATOM 2122 CB ASN A 278 69.145 23.456 −13.544 1.00 71.99 A C ATOM 2123 CG ASN A 278 69.124 24.372 −14.749 1.00 73.02 A C ATOM 2124 OD1 ASN A 278 68.090 24.528 −15.397 1.00 75.67 A O ATOM 2125 ND2 ASN A 278 70.261 25.002 −15.043 1.00 71.03 A N ATOM 2126 N ILE A 279 69.567 23.002 −10.164 1.00 67.52 A N ATOM 2127 CA ILE A 279 69.188 22.191 −9.006 1.00 66.60 A C ATOM 2128 C ILE A 279 68.277 22.978 −8.046 1.00 63.12 A C ATOM 2129 O ILE A 279 67.509 22.382 −7.293 1.00 61.43 A O ATOM 2130 CB ILE A 279 70.451 21.673 −8.266 1.00 69.14 A C ATOM 2131 CG1 ILE A 279 71.311 20.801 −9.196 1.00 70.33 A C ATOM 2132 CG2 ILE A 279 70.069 20.890 −7.004 1.00 70.79 A C ATOM 2133 CD1 ILE A 279 70.601 19.582 −9.773 1.00 71.75 A C ATOM 2134 N PHE A 280 68.364 24.310 −8.089 1.00 58.16 A N ATOM 2135 CA PHE A 280 67.577 25.184 −7.215 1.00 54.73 A C ATOM 2136 C PHE A 280 66.327 25.723 −7.929 1.00 48.44 A C ATOM 2137 O PHE A 280 66.404 26.160 −9.065 1.00 42.63 A O ATOM 2138 CB PHE A 280 68.440 26.352 −6.737 1.00 54.07 A C ATOM 2139 CG PHE A 280 69.641 25.934 −5.950 1.00 56.01 A C ATOM 2140 CD1 PHE A 280 70.860 25.735 −6.582 1.00 56.28 A C ATOM 2141 CD2 PHE A 280 69.554 25.741 −4.578 1.00 56.86 A C ATOM 2142 CE1 PHE A 280 71.975 25.351 −5.861 1.00 58.79 A C ATOM 2143 CE2 PHE A 280 70.663 25.351 −3.846 1.00 58.48 A C ATOM 2144 CZ PHE A 280 71.880 25.158 −4.487 1.00 58.24 A C ATOM 2145 N PRO A 281 65.183 25.713 −7.253 1.00 46.45 A N ATOM 2146 CA PRO A 281 63.933 26.153 −7.873 1.00 45.34 A C ATOM 2147 C PRO A 281 63.830 27.670 −7.930 1.00 46.32 A C ATOM 2148 O PRO A 281 64.540 28.377 −7.209 1.00 44.85 A O ATOM 2149 CB PRO A 281 62.875 25.625 −6.911 1.00 47.02 A C ATOM 2159 CG PRO A 281 63.552 25.707 −5.574 1.00 48.68 A C ATOM 2151 CD PRO A 281 64.985 25.312 −5.845 1.00 47.62 A C ATOM 2152 N VAL A 282 62.942 28.158 −8.783 1.00 44.02 A N ATOM 2153 CA VAL A 282 62.594 29.567 −8.785 1.00 44.12 A C ATOM 2154 C VAL A 282 61.625 29.811 −7.650 1.00 44.35 A C ATOM 2155 O VAL A 282 60.976 28.886 −7.174 1.00 43.30 A O ATOM 2156 CB VAL A 282 61.977 30.021 −10.119 1.00 44.10 A C ATOM 2157 CG1 VAL A 282 62.930 29.754 −11.259 1.00 40.34 A C ATOM 2158 CG2 VAL A 282 60.621 29.359 −10.368 1.00 48.29 A C ATOM 2159 N ILE A 283 61.555 31.048 −7.186 1.00 40.14 A N ATOM 2160 CA ILE A 283 60.502 31.421 −6.273 1.00 42.52 A C ATOM 2161 C ILE A 283 59.656 32.479 −6.970 1.00 39.13 A C ATOM 2162 O ILE A 283 60.171 33.297 −7.743 1.00 35.09 A O ATOM 2163 CB ILE A 283 61.043 31.847 −4.878 1.00 43.69 A C ATOM 2164 CG1 ILE A 283 59.925 32.432 −4.023 1.00 46.75 A C ATOM 2165 CG2 ILE A 283 62.174 32.818 −4.984 1.00 47.57 A C ATOM 2166 CD1 ILE A 283 60.216 32.406 −2.547 1.00 47.98 A C ATOM 2167 N SER A 284 58.350 32.359 −6.758 1.00 35.81 A N ATOM 2168 CA SER A 284 57.354 33.282 −7.292 1.00 33.91 A C ATOM 2169 C SER A 284 56.555 33.814 −6.121 1.00 32.23 A C ATOM 2170 O SER A 284 56.080 33.051 −5.274 1.00 31.03 A O ATOM 2171 CB SER A 284 56.457 32.574 −8.313 1.00 31.65 A C ATOM 2172 OG SER A 284 57.075 32.546 −9.585 1.00 35.60 A O ATOM 2173 N LEU A 285 56.455 35.137 −6.028 1.00 25.42 A N ATOM 2174 CA LEU A 285 55.588 35.760 −5.069 1.00 24.59 A C ATOM 2175 C LEU A 285 54.478 36.397 −5.890 1.00 21.13 A C ATOM 2176 O LEU A 285 54.770 37.108 −6.839 1.00 19.53 A O ATOM 2177 CB LEU A 285 56.348 36.799 −4.263 1.00 27.87 A C ATOM 2178 CG LEU A 285 57.674 36.297 −3.682 1.00 27.04 A C ATOM 2179 CD1 LEU A 285 58.356 37.456 −3.002 1.00 31.32 A C ATOM 2180 CD2 LEU A 285 57.428 35.159 −2.702 1.00 29.67 A C ATOM 2181 N TYR A 286 53.233 36.065 −5.587 1.00 22.23 A N ATOM 2182 CA TYR A 286 52.112 36.768 −6.196 1.00 22.87 A C ATOM 2183 C TYR A 286 51.807 37.909 −5.280 1.00 20.51 A C ATOM 2184 O TYR A 286 51.686 37.712 −4.069 1.00 23.12 A O ATOM 2185 CB TYR A 286 50.871 35.898 −6.336 1.00 18.84 A C ATOM 2186 CG TYR A 286 50.989 34.755 −7.339 1.00 20.36 A C ATOM 2187 CD1 TYR A 286 51.857 33.691 −7.125 1.00 27.97 A C ATOM 2188 CD2 TYR A 286 50.168 34.720 −8.477 1.00 22.74 A C ATOM 2189 CE1 TYR A 286 51.937 32.641 −8.024 1.00 28.14 A C ATOM 2190 CE2 TYR A 286 50.243 33.661 −9.393 1.00 19.26 A C ATOM 2191 CZ TYR A 286 51.125 32.630 −9.148 1.00 24.29 A C ATOM 2192 OH TYR A 286 51.198 31.595 −10.033 1.00 23.89 A O ATOM 2193 N LEU A 287 51.672 39.113 −5.849 1.00 17.57 A N ATOM 2194 CA LEU A 287 51.327 40.293 −5.084 1.00 18.37 A C ATOM 2195 C LEU A 287 49.902 40.714 −5.367 1.00 19.30 A C ATOM 2196 O LEU A 287 49.413 40.525 −6.486 1.00 17.31 A O ATOM 2197 CB LEU A 287 52.291 41.429 −5.435 1.00 16.99 A C ATOM 2198 CG LEU A 287 53.759 41.076 −5.143 1.00 19.76 A C ATOM 2199 CD1 LEU A 287 54.689 42.131 −5.672 1.00 21.23 A C ATOM 2200 CD2 LEU A 287 53.943 40.852 −3.653 1.00 27.06 A C ATOM 2201 N MET A 288 49.250 41.310 −4.369 1.00 17.49 A N ATOM 2202 CA MET A 288 47.906 41.869 −4.524 1.00 14.88 A C ATOM 2203 C MET A 288 47.938 42.861 −5.688 1.00 17.43 A C ATOM 2204 O MET A 288 48.833 43.675 −5.798 1.00 16.72 A O ATOM 2205 CB MET A 288 47.471 42.597 −3.242 1.00 19.44 A C ATOM 2206 CG MET A 288 46.150 43.315 −3.360 1.00 21.18 A C ATOM 2207 SD MET A 288 45.656 44.123 −1.787 1.00 27.75 A S ATOM 2208 CE MET A 288 45.045 42.809 −0.930 1.00 26.84 A C ATOM 2209 N GLY A 289 46.961 42.792 −6.574 1.00 15.66 A N ATOM 2210 CA GLY A 289 46.942 43.753 −7.664 1.00 17.02 A C ATOM 2211 C GLY A 289 46.143 45.000 −7.381 1.00 16.69 A C ATOM 2212 O GLY A 289 45.655 45.211 −6.267 1.00 16.95 A O ATOM 2213 N GLU A 290 45.922 45.786 −8.425 1.00 16.66 A N ATOM 2214 CA GLU A 290 45.190 47.057 −8.298 1.00 17.93 A C ATOM 2215 C GLU A 290 43.656 46.888 −8.251 1.00 18.47 A C ATOM 2216 O GLU A 290 42.944 47.782 −7.800 1.00 20.92 A O ATOM 2217 CB GLU A 290 45.541 47.958 −9.465 1.00 21.26 A C ATOM 2292 O THR A 299 61.614 36.337 −11.139 1.00 28.84 A O ATOM 2293 CB THR A 299 59.291 34.640 −11.560 1.00 27.03 A C ATOM 2294 OG1 THR A 299 57.902 34.287 −11.572 1.00 32.46 A O ATOM 2295 CG2 THR A 299 60.001 33.283 −11.620 1.00 28.77 A C ATOM 2296 N ILE A 300 61.803 35.268 −9.175 1.00 31.26 A N ATOM 2297 CA ILE A 300 63.270 35.393 −9.098 1.00 33.70 A C ATOM 2298 C ILE A 300 63.938 34.033 −9.195 1.00 39.02 A C ATOM 2299 O ILE A 300 63.273 32.989 −9.287 1.00 37.86 A O ATOM 2300 CB ILE A 300 63.729 36.107 −7.793 1.00 35.95 A C ATOM 2301 CG1 ILE A 300 63.443 35.258 −6.566 1.00 37.33 A C ATOM 2302 CG2 ILE A 300 63.049 37.457 −7.639 1.00 35.67 A C ATOM 2303 CD1 ILE A 300 64.152 35.715 −5.318 1.00 39.22 A C ATOM 2304 N LEU A 301 65.265 34.067 −9.161 1.00 39.05 A N ATOM 2305 CA LEU A 301 66.093 32.901 −9.421 1.00 37.54 A C ATOM 2306 C LEU A 301 67.013 32.602 −8.255 1.00 38.40 A C ATOM 2307 O LEU A 301 67.182 33.428 −7.371 1.00 36.53 A O ATOM 2308 CB LEU A 301 66.933 33.169 −10.664 1.00 36.30 A C ATOM 2309 CG LEU A 301 66.126 33.447 −11.937 1.00 34.74 A C ATOM 2310 CD1 LEU A 301 67.030 33.935 −13.022 1.00 32.47 A C ATOM 2311 CD2 LEU A 301 65.387 32.196 −12.430 1.00 39.84 A C ATOM 2312 N PRO A 302 67.619 31.420 −8.264 1.00 39.73 A N ATOM 2313 CA PRO A 302 68.706 31.113 −7.335 1.00 41.84 A C ATOM 2314 C PRO A 302 69.828 32.157 −7.387 1.00 41.87 A C ATOM 2315 O PRO A 302 70.427 32.420 −6.356 1.00 45.40 A O ATOM 2316 CB PRO A 302 69.208 29.759 −7.834 1.00 41.99 A C ATOM 2317 CG PRO A 302 68.031 29.157 −8.495 1.00 42.63 A C ATOM 2318 CD PRO A 302 67.321 30.285 −9.150 1.00 40.17 A C ATOM 2319 N GLN A 303 70.094 32.759 −8.546 1.00 40.21 A N ATOM 2320 CA GLN A 303 71.197 33.721 −8.659 1.00 41.56 A C ATOM 2321 C GLN A 303 70.933 34.984 −7.824 1.00 43.24 A C ATOM 2322 O GLN A 303 71.837 35.788 −7.598 1.00 38.56 A O ATOM 2323 CB GLN A 303 71.523 34.117 −10.119 1.00 44.66 A C ATOM 2324 CG GLN A 303 70.564 33.666 −11.201 1.00 47.40 A C ATOM 2325 CD GLN A 303 70.716 32.201 −11.545 1.00 50.63 A C ATOM 2326 OE1 GLN A 303 69.911 31.372 −11.120 1.00 55.64 A O ATOM 2327 NE2 GLN A 303 71.742 31.877 −12.332 1.00 51.86 A N ATOM 2328 N GLN A 304 69.689 35.145 −7.382 1.00 41.50 A N ATOM 2329 CA GLN A 304 69.273 36.282 −6.589 1.00 46.43 A C ATOM 2330 C GLN A 304 69.293 35.906 −5.100 1.00 47.20 A C ATOM 2331 O GLN A 304 69.738 36.705 −4.270 1.00 45.43 A O ATOM 2332 CB GLN A 304 67.871 36.735 −7.046 1.00 49.88 A C ATOM 2333 CG GLN A 304 67.862 37.811 −8.157 1.00 51.33 A C ATOM 2334 CD GLN A 304 68.273 37.315 −9.548 1.00 54.63 A C ATOM 2335 OE1 GLN A 304 67.918 37.933 −10.556 1.00 54.99 A O ATOM 2336 NE2 GLN A 304 69.031 36.224 −9.607 1.00 57.60 A N ATOM 2337 N TYR A 305 68.838 34.694 −4.760 1.00 47.73 A N ATOM 2338 CA TYR A 305 68.895 34.241 −3.364 1.00 51.85 A C ATOM 2339 C TYR A 305 70.132 33.385 −3.029 1.00 53.38 A C ATOM 2340 O TYR A 305 70.267 32.911 −1.903 1.00 53.57 A O ATOM 2341 CB TYR A 305 67.573 33.577 −2.910 1.00 52.81 A C ATOM 2342 CG TYR A 305 67.247 32.202 −3.471 1.00 53.16 A C ATOM 2343 CD1 TYR A 305 67.828 31.052 −2.943 1.00 52.42 A C ATOM 2344 CD2 TYR A 305 66.309 32.053 −4.494 1.00 52.93 A C ATOM 2345 CE1 TYR A 305 67.515 29.789 −3.446 1.00 53.23 A C ATOM 2346 CE2 TYR A 305 65.985 30.796 −5.002 1.00 53.91 A C ATOM 2347 CZ TYR A 305 66.592 29.669 −4.474 1.00 53.62 A C ATOM 2348 OH TYR A 305 66.272 28.425 −4.971 1.00 53.84 A O ATOM 2349 N LEU A 306 71.033 33.228 −3.997 1.00 55.03 A N ATOM 2350 CA LEU A 306 72.355 32.633 −3.777 1.00 61.56 A C ATOM 2351 C LEU A 306 73.390 33.700 −4.150 1.00 63.69 A C ATOM 2352 O LEU A 306 73.663 33.946 −5.332 1.00 64.04 A O ATOM 2353 CB LEU A 306 72.559 31.361 −4.610 1.00 62.70 A C ATOM 2354 CG LEU A 306 72.418 29.992 −3.934 1.00 65.11 A C ATOM 2355 CD1 LEU A 306 71.256 29.932 −2.950 1.00 65.92 A C ATOM 2356 CD2 LEU A 306 72.262 28.920 −5.001 1.00 65.99 A C ATOM 2357 N ARG A 307 73.965 34.321 −3.126 1.00 67.42 A N ATOM 2358 CA ARG A 307 74.753 35.546 −3.285 1.00 69.54 A C ATOM 2359 C ARG A 307 76.226 35.241 −3.045 1.00 70.36 A C ATOM 2360 O ARG A 307 76.568 34.726 −1.981 1.00 69.95 A O ATOM 2361 CB ARG A 307 74.270 36.631 −2.302 1.00 70.52 A C ATOM 2362 CG ARG A 307 73.942 36.126 −0.885 1.00 71.76 A C ATOM 2363 CD ARG A 307 73.347 37.158 0.060 1.00 71.91 A C ATOM 2364 NE ARG A 307 74.308 37.604 1.064 1.00 71.58 A N ATOM 2365 CZ ARG A 307 75.160 38.609 0.900 1.00 72.31 A C ATOM 2440 OD2 ASP A 317 87.616 26.284 −4.381 1.00 83.59 A O ATOM 2441 N ASP A 318 84.113 29.504 −5.421 1.00 77.10 A N ATOM 2442 CA ASP A 318 82.894 30.315 −5.525 1.00 76.86 A C ATOM 2443 C ASP A 318 81.909 29.982 −4.398 1.00 75.04 A C ATOM 2444 O ASP A 318 81.025 29.137 −4.565 1.00 76.20 A O ATOM 2445 CB ASP A 318 82.212 30.093 −6.880 1.00 76.77 A C ATOM 2446 CG ASP A 318 83.043 30.590 −8.044 1.00 77.69 A C ATOM 2447 OD1 ASP A 318 84.270 30.781 −7.874 1.00 78.53 A O ATOM 2448 OD2 ASP A 318 82.550 30.811 −9.170 1.00 77.17 A O ATOM 2449 N CYS A 319 82.065 30.653 −3.259 1.00 73.01 A N ATOM 2450 CA CYS A 319 81.211 30.428 −2.094 1.00 71.05 A C ATOM 2451 C CYS A 319 80.044 31.414 −2.062 1.00 68.67 A C ATOM 2452 O CYS A 319 80.235 32.611 −2.258 1.00 66.66 A O ATOM 2453 CB CYS A 319 82.026 30.554 −0.803 1.00 71.92 A C ATOM 2454 SG CYS A 319 83.414 29.394 −0.686 1.00 74.09 A S ATOM 2455 N TYR A 320 78.839 30.899 −1.832 1.00 66.44 A N ATOM 2456 CA TYR A 320 77.645 31.728 −1.691 1.00 64.22 A C ATOM 2457 C TYR A 320 77.013 31.498 −0.320 1.00 62.66 A C ATOM 2458 O TYR A 320 77.332 30.523 0.365 1.00 61.41 A O ATOM 2459 CB TYR A 320 76.611 31.384 −2.764 1.00 64.24 A C ATOM 2460 CG TYR A 320 77.108 31.323 −4.198 1.00 64.74 A C ATOM 2461 CD1 TYR A 320 77.957 30.302 −4.632 1.00 64.73 A C ATOM 2462 CD2 TYR A 320 76.682 32.260 −5.139 1.00 64.78 A C ATOM 2463 CE1 TYR A 320 78.390 30.239 −5.961 1.00 64.57 A C ATOM 2464 CE2 TYR A 320 77.106 32.202 −6.465 1.00 64.30 A C ATOM 2465 CZ TYR A 320 77.957 31.193 −6.871 1.00 64.35 A C ATOM 2466 OH TYR A 320 78.374 31.146 −8.185 1.00 62.89 A O ATOM 2467 N LYS A 321 76.111 32.392 0.076 1.00 59.11 A N ATOM 2468 CA LYS A 321 75.320 32.189 1.286 1.00 58.36 A C ATOM 2469 C LYS A 321 73.816 32.265 0.996 1.00 55.24 A C ATOM 2470 O LYS A 321 73.353 33.065 0.181 1.00 47.87 A O ATOM 2471 CB LYS A 321 75.747 33.160 2.398 1.00 59.88 A C ATOM 2472 CG LYS A 321 74.853 34.371 2.629 1.00 62.72 A C ATOM 2473 CD LYS A 321 75.277 35.120 3.888 1.00 64.37 A C ATOM 2474 CE LYS A 321 74.699 34.483 5.145 1.00 64.91 A C ATOM 2475 NZ LYS A 321 74.999 35.289 6.363 1.00 66.23 A N ATOM 2476 N PHE A 322 73.062 31.401 1.664 1.00 51.88 A N ATOM 2477 CA PHE A 322 71.619 31.397 1.531 1.00 49.73 A C ATOM 2478 C PHE A 322 71.087 32.737 2.019 1.00 49.06 A C ATOM 2479 O PHE A 322 71.346 33.148 3.154 1.00 45.51 A O ATOM 2480 CB PHE A 322 70.999 30.235 2.321 1.00 49.10 A C ATOM 2481 CG PHE A 322 69.573 29.925 1.935 1.00 44.63 A C ATOM 2482 CD1 PHE A 322 68.563 29.921 2.894 1.00 45.73 A C ATOM 2483 CD2 PHE A 322 69.248 29.629 0.623 1.00 39.25 A C ATOM 2484 CE1 PHE A 322 67.252 29.634 2.539 1.00 44.70 A C ATOM 2485 CE2 PHE A 322 67.950 29.351 0.261 1.00 41.50 A C ATOM 2486 CZ PHE A 322 66.947 29.353 1.218 1.00 42.07 A C ATOM 2487 N ALA A 323 70.339 33.399 1.142 1.00 47.94 A N ATOM 2488 CA ALA A 323 69.901 34.771 1.336 1.00 46.61 A C ATOM 2489 C ALA A 323 68.426 34.839 1.712 1.00 44.07 A C ATOM 2490 O ALA A 323 67.809 35.887 1.548 1.00 33.93 A O ATOM 2491 CB ALA A 323 70.133 35.564 0.054 1.00 49.38 A C ATOM 2492 N ILE A 324 67.853 33.725 2.169 1.00 37.73 A N ATOM 2493 CA ILE A 324 66.520 33.746 2.739 1.00 38.21 A C ATOM 2494 C ILE A 324 66.643 33.442 4.214 1.00 34.73 A C ATOM 2495 O ILE A 324 67.442 32.611 4.619 1.00 36.43 A O ATOM 2496 CB ILE A 324 65.577 32.736 2.038 1.00 38.89 A C ATOM 2497 CG1 ILE A 324 65.714 32.862 0.518 1.00 38.34 A C ATOM 2498 CG2 ILE A 324 64.126 32.960 2.495 1.00 40.76 A C ATOM 2499 CD1 ILE A 324 64.684 32.110 −0.277 1.00 41.65 A C ATOM 2500 N SER A 325 65.840 34.112 5.020 1.00 32.69 A N ATOM 2501 CA SER A 325 66.013 34.031 6.460 1.00 38.71 A C ATOM 2502 C SER A 325 64.722 34.407 7.139 1.00 39.64 A C ATOM 2503 O SER A 325 63.792 34.883 6.509 1.00 40.29 A O ATOM 2504 CB SER A 325 67.150 34.953 6.925 1.00 40.03 A C ATOM 2505 OG SER A 325 66.788 36.327 6.838 1.00 38.81 A O ATOM 2506 N GLN A 326 64.677 34.221 8.440 1.00 38.99 A N ATOM 2507 CA GLN A 326 63.414 34.244 9.134 1.00 39.09 A C ATOM 2508 C GLN A 326 63.294 35.561 9.885 1.00 36.76 A C ATOM 2509 O GLN A 326 64.259 36.297 10.004 1.00 39.83 A O ATOM 2510 CB GLN A 326 63.287 33.011 10.037 1.00 41.88 A C ATOM 2511 CG GLN A 326 64.481 32.024 9.957 1.00 45.10 A C ATOM 2512 CD GLN A 326 64.374 30.817 10.892 1.00 50.52 A C ATOM 2513 OE1 GLN A 326 65.393 30.286 11.322 1.00 51.97 A O ATOM 2514 NE2 GLN A 326 63.151 30.388 11.202 1.00 51.73 A N ATOM 2515 N SER A 327 62.108 35.878 10.374 1.00 30.92 A N ATOM 2516 CA SER A 327 61.904 37.188 10.988 1.00 35.17 A C ATOM 2517 C SER A 327 60.788 37.140 11.993 1.00 36.09 A C ATOM 2518 O SER A 327 59.978 36.208 12.018 1.00 38.75 A O ATOM 2519 CB SER A 327 61.578 38.259 9.921 1.00 35.42 A C ATOM 2520 OG SER A 327 60.882 39.380 10.482 1.00 33.54 A O ATOM 2521 N SER A 328 60.723 38.174 12.808 1.00 31.04 A N ATOM 2522 CA SER A 328 59.597 38.328 13.697 1.00 37.93 A C ATOM 2523 C SER A 328 58.868 39.654 13.520 1.00 39.07 A C ATOM 2524 O SER A 328 57.960 39.967 14.296 1.00 43.35 A O ATOM 2525 CB SER A 328 60.086 38.167 15.123 1.00 41.74 A C ATOM 2526 OG SER A 328 60.967 39.227 15.485 1.00 45.41 A O ATOM 2527 N THR A 329 59.257 40.409 12.492 1.00 37.31 A N ATOM 2528 CA THR A 329 58.675 41.715 12.186 1.00 40.83 A C ATOM 2529 C THR A 329 58.020 41.703 10.797 1.00 39.53 A C ATOM 2530 O THR A 329 57.814 42.771 10.218 1.00 37.06 A O ATOM 2531 CB THR A 329 59.770 42.814 12.193 1.00 42.95 A C ATOM 2532 OG1 THR A 329 60.831 42.455 11.287 1.00 41.26 A O ATOM 2533 CG2 THR A 329 60.441 42.933 13.558 1.00 44.90 A C ATOM 2534 N GLY A 330 57.724 40.510 10.270 1.00 37.04 A N ATOM 2535 CA GLY A 330 57.032 40.358 8.988 1.00 35.68 A C ATOM 2536 C GLY A 330 57.929 39.930 7.836 1.00 34.85 A C ATOM 2537 O GLY A 330 59.067 39.526 8.047 1.00 32.50 A O ATOM 2538 N THR A 331 57.398 39.974 6.605 1.00 33.39 A N ATOM 2539 CA THR A 331 58.207 39.709 5.419 1.00 28.89 A C ATOM 2540 C THR A 331 58.979 40.971 4.998 1.00 27.79 A C ATOM 2541 O THR A 331 58.496 42.086 5.175 1.00 33.40 A O ATOM 2542 CB THR A 331 57.320 39.267 4.249 1.00 30.99 A C ATOM 2543 OG1 THR A 331 56.695 38.020 4.561 1.00 30.88 A O ATOM 2544 CG2 THR A 331 58.157 38.989 2.983 1.00 33.73 A C ATOM 2545 N VAL A 332 60.177 40.764 4.470 1.00 22.23 A N ATOM 2546 CA VAL A 332 61.065 41.847 3.989 1.00 27.82 A C ATOM 2547 C VAL A 332 61.630 41.466 2.632 1.00 24.10 A C ATOM 2548 O VAL A 332 62.394 40.540 2.501 1.00 26.31 A O ATOM 2549 CB VAL A 332 62.274 42.139 4.935 1.00 28.52 A C ATOM 2550 CG1 VAL A 332 63.138 43.293 4.367 1.00 32.83 A C ATOM 2551 CG2 VAL A 332 61.801 42.468 6.329 1.00 30.87 A C ATOM 2552 N MET A 333 61.242 42.199 1.591 1.00 29.37 A N ATOM 2553 CA MET A 333 61.760 41.968 0.251 1.00 23.35 A C ATOM 2554 C MET A 333 63.012 42.813 −0.015 1.00 26.09 A C ATOM 2555 O MET A 333 62.920 43.935 −0.512 1.00 22.66 A O ATOM 2556 CB MET A 333 60.687 42.296 −0.804 1.00 26.84 A C ATOM 2557 CG MET A 333 59.550 41.295 −0.855 1.00 28.90 A C ATOM 2558 SD MET A 333 58.086 41.883 −1.807 1.00 33.93 A S ATOM 2559 CE MET A 333 58.640 41.701 −3.325 1.00 30.83 A C ATOM 2560 N GLY A 334 64.179 42.265 0.294 1.00 26.44 A N ATOM 2561 CA GLY A 334 65.428 43.015 0.190 1.00 28.29 A C ATOM 2562 C GLY A 334 66.044 43.002 −1.185 1.00 28.85 A C ATOM 2563 O GLY A 334 65.370 42.791 −2.185 1.00 28.04 A O ATOM 2564 N ALA A 335 67.350 43.220 −1.243 1.00 29.46 A N ATOM 2565 CA ALA A 335 68.097 43.214 −2.489 1.00 28.30 A C ATOM 2566 C ALA A 335 67.939 41.952 −3.330 1.00 31.11 A C ATOM 2567 O ALA A 335 68.001 42.021 −4.563 1.00 29.82 A O ATOM 2568 CB ALA A 335 69.578 43.470 −2.206 1.00 34.20 A C ATOM 2569 N VAL A 336 67.738 40.805 −2.671 1.00 31.66 A N ATOM 2570 CA VAL A 336 67.506 39.532 −3.349 1.00 35.42 A C ATOM 2571 C VAL A 336 66.412 39.733 −4.393 1.00 32.46 A C ATOM 2572 O VAL A 336 66.626 39.464 −5.574 1.00 36.08 A O ATOM 2573 CB VAL A 336 67.096 38.405 −2.341 1.00 38.14 A C ATOM 2574 CG1 VAL A 336 66.466 37.196 −3.057 1.00 41.63 A C ATOM 2575 CG2 VAL A 336 68.294 37.960 −1.518 1.00 42.38 A C ATOM 2576 N ILE A 337 65.271 40.248 −3.944 1.00 32.57 A N ATOM 2577 CA ILE A 337 64.130 40.507 −4.832 1.00 31.81 A C ATOM 2578 C ILE A 337 64.389 41.687 −5.760 1.00 29.91 A C ATOM 2579 O ILE A 337 64.231 41.592 −6.969 1.00 27.22 A O ATOM 2580 CB ILE A 337 62.835 40.731 −4.005 1.00 34.05 A C ATOM 2581 CG1 ILE A 337 62.466 39.472 −3.216 1.00 37.53 A C ATOM 2582 CG2 ILE A 337 61.668 41.174 −4.903 1.00 34.31 A C ATOM 2583 CD1 ILE A 337 61.814 38.383 −4.043 1.00 39.14 A C ATOM 2584 N MET A 338 64.813 42.816 −5.202 1.00 28.42 A N ATOM 2585 CA MET A 338 64.909 44.038 −5.998 1.00 27.14 A C ATOM 2586 C MET A 338 65.914 43.969 −7.154 1.00 28.91 A C ATOM 2587 O MET A 338 65.753 44.650 −8.166 1.00 28.30 A O ATOM 2588 CB MET A 338 65.195 45.214 −5.067 1.00 25.93 A C ATOM 2589 CG MET A 338 64.083 45.457 −4.082 1.00 27.03 A C ATOM 2590 SD MET A 338 64.367 46.907 −3.076 1.00 25.07 A S ATOM 2591 CE MET A 338 64.174 48.235 −4.312 1.00 20.81 A C ATOM 2592 N GLU A 339 66.954 43.142 −7.040 1.00 29.81 A N ATOM 2593 CA GLU A 339 67.909 43.018 −8.142 1.00 32.30 A C ATOM 2594 C GLU A 339 67.318 42.371 −9.403 1.00 30.06 A C ATOM 2595 O GLU A 339 67.874 42.502 −10.488 1.00 33.61 A O ATOM 2596 CB GLU A 339 69.174 42.269 −7.704 1.00 33.90 A C ATOM 2597 CG GLU A 339 70.197 43.177 −7.027 1.00 38.40 A C ATOM 2598 CD GLU A 339 71.139 42.424 −6.107 1.00 42.07 A C ATOM 2599 OE1 GLU A 339 71.439 41.242 −6.391 1.00 39.96 A O ATOM 2600 OE2 GLU A 339 71.570 43.015 −5.095 1.00 43.98 A O ATOM 2601 N GLY A 340 66.187 41.687 −9.259 1.00 30.73 A N ATOM 2602 CA GLY A 340 65.475 41.165 −10.411 1.00 29.00 A C ATOM 2603 C GLY A 340 64.626 42.169 −11.162 1.00 25.72 A C ATOM 2604 O GLY A 340 64.289 41.949 −12.331 1.00 25.52 A O ATOM 2605 N PHE A 341 64.278 43.281 −10.509 1.00 21.32 A N ATOM 2606 CA PHE A 341 63.243 44.173 −11.017 1.00 17.05 A C ATOM 2607 C PHE A 341 63.561 45.656 −10.971 1.00 19.54 A C ATOM 2608 O PHE A 341 64.379 46.111 −10.174 1.00 20.37 A O ATOM 2609 CB PHE A 341 61.961 43.899 −10.222 1.00 18.19 A C ATOM 2610 CG PHE A 341 61.630 42.440 −10.137 1.00 20.96 A C ATOM 2611 CD1 PHE A 341 61.108 41.770 −11.237 1.00 22.17 A C ATOM 2612 CD2 PHE A 341 61.910 41.717 −8.998 1.00 23.21 A C ATOM 2613 CE1 PHE A 341 60.853 40.399 −11.160 1.00 17.74 A C ATOM 2614 CE2 PHE A 341 61.650 40.351 −8.939 1.00 23.34 A C ATOM 2615 CZ PHE A 341 61.134 39.705 −10.012 1.00 24.23 A C ATOM 2616 N TYR A 342 62.952 46.413 −11.875 1.00 17.67 A N ATOM 2617 CA TYR A 342 62.820 47.837 −11.702 1.00 17.52 A C ATOM 2618 C TYR A 342 61.608 48.077 −10.810 1.00 22.25 A C ATOM 2619 O TYR A 342 60.494 47.620 −11.100 1.00 19.30 A O ATOM 2620 CB TYR A 342 62.656 48.485 −13.040 1.00 17.92 A C ATOM 2621 CG TYR A 342 62.654 49.980 −13.067 1.00 18.37 A C ATOM 2622 CD1 TYR A 342 63.668 50.730 −12.467 1.00 19.68 A C ATOM 2623 CD2 TYR A 342 61.681 50.654 −13.765 1.00 23.05 A C ATOM 2624 CE1 TYR A 342 63.684 52.115 −12.562 1.00 22.84 A C ATOM 2625 CE2 TYR A 342 61.693 52.006 −13.868 1.00 22.40 A C ATOM 2626 CZ TYR A 342 62.693 52.750 −13.264 1.00 22.81 A C ATOM 2627 OH TYR A 342 62.667 54.131 −13.385 1.00 26.20 A O ATOM 2628 N VAL A 343 61.840 48.777 −9.705 1.00 15.05 A N ATOM 2629 CA VAL A 343 60.827 49.008 −8.688 1.00 17.53 A C ATOM 2630 C VAL A 343 60.510 50.494 −8.598 1.00 14.20 A C ATOM 2631 O VAL A 343 61.378 51.334 −8.376 1.00 15.91 A O ATOM 2632 CB VAL A 343 61.259 48.442 −7.305 1.00 15.41 A C ATOM 2633 CG1 VAL A 343 60.123 48.560 −6.267 1.00 18.03 A C ATOM 2634 CG2 VAL A 343 61.704 47.022 −7.473 1.00 18.07 A C ATOM 2635 N VAL A 344 59.231 50.791 −8.767 1.00 11.66 A N ATOM 2636 CA VAL A 344 58.682 52.123 −8.783 1.00 12.22 A C ATOM 2637 C VAL A 344 57.903 52.401 −7.510 1.00 13.35 A C ATOM 2638 O VAL A 344 56.875 51.802 −7.235 1.00 16.24 A O ATOM 2639 CB VAL A 344 57.774 52.308 −10.027 1.00 15.89 A C ATOM 2640 CG1 VAL A 344 57.159 53.685 −10.035 1.00 18.74 A C ATOM 2641 CG2 VAL A 344 58.587 52.106 −11.280 1.00 18.50 A C ATOM 2642 N PHE A 345 58.418 53.322 −6.713 1.00 16.40 A N ATOM 2643 CA PHE A 345 57.771 53.763 −5.483 1.00 15.06 A C ATOM 2644 C PHE A 345 56.833 54.934 −5.754 1.00 15.39 A C ATOM 2645 O PHE A 345 57.192 56.113 −5.655 1.00 17.43 A O ATOM 2646 CB PHE A 345 58.846 54.062 −4.416 1.00 17.40 A C ATOM 2647 CG PHE A 345 59.670 52.855 −4.040 1.00 15.11 A C ATOM 2648 CD1 PHE A 345 60.702 52.386 −4.863 1.00 13.07 A C ATOM 2649 CD2 PHE A 345 59.402 52.153 −2.882 1.00 13.71 A C ATOM 2650 CE1 PHE A 345 61.446 51.242 −4.510 1.00 15.84 A C ATOM 2651 CE2 PHE A 345 60.169 51.040 −2.507 1.00 11.40 A C ATOM 2652 CZ PHE A 345 61.186 50.581 −3.327 1.00 15.67 A C ATOM 2653 N ASP A 346 55.633 54.601 −6.206 1.00 16.44 A N ATOM 2654 CA ASP A 346 54.671 55.593 −6.672 1.00 15.35 A C ATOM 2655 C ASP A 346 53.855 56.101 −5.495 1.00 16.03 A C ATOM 2656 O ASP A 346 52.711 55.700 −5.254 1.00 19.50 A O ATOM 2657 CB ASP A 346 53.800 54.986 −7.778 1.00 18.03 A C ATOM 2658 CG ASP A 346 52.872 55.995 −8.420 1.00 25.99 A C ATOM 2659 OD1 ASP A 346 52.844 57.166 −7.967 1.00 28.56 A O ATOM 2660 OD2 ASP A 346 52.120 55.680 −9.382 1.00 23.57 A O ATOM 2661 N ARG A 347 54.491 56.978 −4.725 1.00 17.55 A N ATOM 2662 CA ARG A 347 53.908 57.497 −3.499 1.00 21.29 A C ATOM 2663 C ARG A 347 52.632 58.294 −3.785 1.00 18.95 A C ATOM 2664 O ARG A 347 51.701 58.266 −2.991 1.00 22.26 A O ATOM 2665 CB ARG A 347 54.932 58.369 −2.765 1.00 19.24 A C ATOM 2666 CG ARG A 347 56.184 57.635 −2.282 1.00 22.31 A C ATOM 2667 CD ARG A 347 57.359 58.594 −2.059 1.00 23.46 A C ATOM 2668 NE ARG A 347 57.009 59.652 −1.092 1.00 23.99 A N ATOM 2669 CZ ARG A 347 57.403 59.691 0.183 1.00 30.72 A C ATOM 2670 NH1 ARG A 347 57.031 60.700 0.959 1.00 32.59 A N ATOM 2671 NH2 ARG A 347 58.174 58.745 0.696 1.00 27.96 A N ATOM 2672 N ALA A 348 52.590 58.959 −4.936 1.00 21.83 A N ATOM 2673 CA ALA A 348 51.439 59.780 −5.327 1.00 24.64 A C ATOM 2674 C ALA A 348 50.148 58.953 −5.399 1.00 28.25 A C ATOM 2675 O ALA A 348 49.056 59.426 −5.028 1.00 24.96 A O ATOM 2676 CB ALA A 348 51.721 60.425 −6.668 1.00 24.31 A C ATOM 2677 N ARG A 349 50.282 57.724 −5.896 1.00 25.65 A N ATOM 2678 CA ARG A 349 49.151 56.806 −6.029 1.00 25.84 A C ATOM 2679 C ARG A 349 49.168 55.627 −5.077 1.00 25.58 A C ATOM 2680 O ARG A 349 48.460 54.653 −5.319 1.00 25.28 A O ATOM 2681 CB ARG A 349 49.100 56.276 −7.459 1.00 29.93 A C ATOM 2682 CG ARG A 349 49.176 57.344 −8.488 1.00 33.60 A C ATOM 2683 CD ARG A 349 48.502 57.000 −9.775 1.00 36.74 A C ATOM 2684 NE ARG A 349 48.827 58.016 −10.763 1.00 42.71 A N ATOM 2685 CZ ARG A 349 48.278 59.227 −10.814 1.00 48.30 A C ATOM 2686 NH1 ARG A 349 47.316 59.600 −9.964 1.00 46.44 A N ATOM 2687 NH2 ARG A 349 48.686 60.072 −11.751 1.00 50.26 A N ATOM 2688 N LYS A 350 49.954 55.721 −3.989 1.00 23.32 A N ATOM 2689 CA LYS A 350 50.022 54.700 −2.945 1.00 24.27 A C ATOM 2690 C LYS A 350 50.163 53.310 −3.549 1.00 19.69 A C ATOM 2691 O LYS A 350 49.374 52.429 −3.260 1.00 20.60 A O ATOM 2692 CB LYS A 350 48.757 54.704 −2.079 1.00 28.78 A C ATOM 2693 CG LYS A 350 48.522 55.929 −1.231 1.00 34.60 A C ATOM 2694 CD LYS A 350 47.436 55.639 −0.141 1.00 37.26 A C ATOM 2695 CE LYS A 350 47.719 54.361 0.695 1.00 36.46 A C ATOM 2696 NZ LYS A 350 46.822 54.210 1.887 1.00 40.30 A N ATOM 2697 N ARG A 351 51.147 53.140 −4.420 1.00 19.35 A N ATOM 2698 CA ARG A 351 51.371 51.855 −5.063 1.00 17.19 A C ATOM 2699 C ARG A 351 52.842 51.641 −5.383 1.00 15.48 A C ATOM 2700 O ARG A 351 53.609 52.576 −5.490 1.00 17.66 A O ATOM 2701 CB ARG A 351 50.501 51.758 −6.328 1.00 15.07 A C ATOM 2702 CG ARG A 351 50.851 52.687 −7.388 1.00 17.01 A C ATOM 2703 CD ARG A 351 49.837 52.667 −8.565 1.00 17.81 A C ATOM 2704 NE ARG A 351 50.304 53.485 −9.674 1.00 17.24 A N ATOM 2705 CZ ARG A 351 49.711 53.543 −10.862 1.00 23.21 A C ATOM 2706 NH1 ARG A 351 48.651 52.804 −11.095 1.00 21.30 A N ATOM 2707 NH2 ARG A 351 50.213 54.312 −11.831 1.00 24.26 A N ATOM 2708 N ILE A 352 53.240 50.376 −5.500 1.00 17.16 A N ATOM 2709 CA ILE A 352 54.581 50.022 −5.928 1.00 16.38 A C ATOM 2710 C ILE A 352 54.510 49.221 −7.208 1.00 15.28 A C ATOM 2711 O ILE A 352 53.800 48.234 −7.277 1.00 15.77 A O ATOM 2712 CB ILE A 352 55.303 49.167 −4.857 1.00 17.10 A C ATOM 2713 CG1 ILE A 352 55.387 49.937 −3.540 1.00 24.67 A C ATOM 2714 CG2 ILE A 352 56.740 48.790 −5.322 1.00 17.46 A C ATOM 2715 CD1 ILE A 352 55.844 49.129 −2.381 1.00 28.46 A C ATOM 2716 N GLY A 353 55.291 49.633 −8.199 1.00 14.93 A N ATOM 2717 CA GLY A 353 55.345 48.949 −9.481 1.00 14.98 A C ATOM 2718 C GLY A 353 56.559 48.090 −9.631 1.00 15.46 A C ATOM 2719 O GLY A 353 57.649 48.466 −9.185 1.00 14.60 A O ATOM 2720 N PHE A 354 56.385 46.936 −10.290 1.00 15.06 A N ATOM 2721 CA PHE A 354 57.469 46.043 −10.577 1.00 14.45 A C ATOM 2722 C PHE A 354 57.482 45.781 −12.064 1.00 15.57 A C ATOM 2723 O PHE A 354 56.431 45.590 −12.685 1.00 17.67 A O ATOM 2724 CB PHE A 354 57.285 44.716 −9.860 1.00 16.68 A C ATOM 2725 CG PHE A 354 57.443 44.793 −8.362 1.00 16.38 A C ATOM 2726 CD1 PHE A 354 56.371 45.164 −7.563 1.00 16.54 A C ATOM 2727 CD2 PHE A 354 58.640 44.430 −7.756 1.00 19.54 A C ATOM 2728 CE1 PHE A 354 56.490 45.231 −6.177 1.00 20.88 A C ATOM 2729 CE2 PHE A 354 58.771 44.487 −6.362 1.00 19.27 A C ATOM 2730 CZ PHE A 354 57.684 44.906 −5.571 1.00 15.66 A C ATOM 2731 N ALA A 355 58.684 45.766 −12.606 1.00 18.28 A N ATOM 2732 CA ALA A 355 58.922 45.384 −13.999 1.00 16.49 A C ATOM 2733 C ALA A 355 60.245 44.644 −14.081 1.00 19.90 A C ATOM 2734 O ALA A 355 61.106 44.777 −13.211 1.00 21.15 A O ATOM 2735 CB ALA A 355 58.922 46.569 −14.878 1.00 17.48 A C ATOM 2736 N VAL A 356 60.399 43.827 −15.120 1.00 20.94 A N ATOM 2737 CA VAL A 356 61.650 43.107 −15.305 1.00 21.72 A C ATOM 2738 C VAL A 356 62.776 44.111 −15.553 1.00 19.54 A C ATOM 2739 O VAL A 356 62.672 44.989 −16.402 1.00 21.35 A O ATOM 2740 CB VAL A 356 61.562 42.087 −16.473 1.00 19.47 A C ATOM 2741 CG1 VAL A 356 62.936 41.435 −16.724 1.00 20.92 A C ATOM 2742 CG2 VAL A 356 60.517 41.025 −16.174 1.00 23.31 A C ATOM 2743 N SER A 357 63.853 43.982 −14.793 1.00 24.48 A N ATOM 2744 CA SER A 357 64.963 44.919 −14.883 1.00 26.30 A C ATOM 2745 C SER A 357 65.767 44.633 −16.142 1.00 26.78 A C ATOM 2746 O SER A 357 66.071 43.481 −16.420 1.00 30.47 A O ATOM 2747 CB SER A 357 65.896 44.775 −13.676 1.00 25.63 A C ATOM 2748 OG SER A 357 67.009 45.645 −13.815 1.00 30.40 A O ATOM 2749 N ALA A 358 66.128 45.682 −16.867 1.00 32.11 A N ATOM 2750 CA ALA A 358 67.012 45.567 −18.029 1.00 36.75 A C ATOM 2751 C ALA A 358 68.445 45.147 −17.666 1.00 38.55 A C ATOM 2752 O ALA A 358 69.233 44.838 −18.560 1.00 42.49 A O ATOM 2753 CB ALA A 358 67.025 46.881 −18.802 1.00 37.17 A C ATOM 2754 N CYS A 359 68.782 45.129 −16.374 1.00 39.61 A N ATOM 2755 CA CYS A 359 70.124 44.742 −15.920 1.00 41.87 A C ATOM 2756 C CYS A 359 70.169 43.490 −15.049 1.00 42.74 A C ATOM 2757 O CYS A 359 71.241 43.132 −14.550 1.00 45.60 A O ATOM 2758 CB CYS A 359 70.801 45.913 −15.175 1.00 41.64 A C ATOM 2759 SG CYS A 359 70.275 46.154 −13.447 1.00 42.44 A S ATOM 2760 N HIS A 360 69.040 42.811 −14.847 1.00 42.50 A N ATOM 2761 CA HIS A 360 69.071 41.569 −14.081 1.00 43.24 A C ATOM 2762 C HIS A 360 69.903 40.538 −14.848 1.00 44.08 A C ATOM 2763 O HIS A 360 69.932 40.545 −16.089 1.00 37.43 A O ATOM 2764 CB HIS A 360 67.665 41.037 −13.772 1.00 43.88 A C ATOM 2765 CG HIS A 360 67.018 40.307 −14.909 1.00 42.46 A C ATOM 2766 ND1 HIS A 360 66.587 40.941 −16.054 1.00 43.80 A N ATOM 2767 CD2 HIS A 360 66.711 38.997 −15.067 1.00 43.40 A C ATOM 2768 CE1 HIS A 360 66.053 40.053 −16.876 1.00 42.29 A C ATOM 2769 NE2 HIS A 360 66.107 38.867 −16.295 1.00 40.67 A N ATOM 2770 N VAL A 361 70.604 39.688 −14.108 1.00 46.31 A N ATOM 2771 CA VAL A 361 71.444 38.671 −14.736 1.00 53.46 A C ATOM 2772 C VAL A 361 70.569 37.519 −15.208 1.00 55.15 A C ATOM 2773 O VAL A 361 69.788 36.965 −14.433 1.00 55.26 A O ATOM 2774 CB VAL A 361 72.584 38.144 −13.812 1.00 55.33 A C ATOM 2775 CG1 VAL A 361 73.724 39.146 −13.769 1.00 58.02 A C ATOM 2776 CG2 VAL A 361 72.086 37.824 −12.392 1.00 57.18 A C ATOM 2777 N HIS A 362 70.687 37.191 −16.491 1.00 58.23 A N ATOM 2778 CA HIS A 362 69.957 36.071 −17.078 1.00 61.27 A C ATOM 2779 C HIS A 362 70.886 35.268 −17.991 1.00 63.90 A C ATOM 2780 O HIS A 362 72.106 35.470 −17.978 1.00 63.06 A O ATOM 2781 CB HIS A 362 68.707 36.570 −17.820 1.00 61.80 A C ATOM 2782 CG HIS A 362 68.987 37.603 −18.869 1.00 64.30 A C ATOM 2783 ND1 HIS A 362 69.075 38.949 −18.582 1.00 65.54 A N ATOM 2784 CD2 HIS A 362 69.176 37.491 −20.206 1.00 66.55 A C ATOM 2785 CE1 HIS A 362 69.318 39.621 −19.694 1.00 66.26 A C ATOM 2786 NE2 HIS A 362 69.384 38.760 −20.694 1.00 67.04 A N ATOM 2787 N ASP A 363 70.311 34.348 −18.765 1.00 66.38 A N ATOM 2788 CA ASP A 363 71.086 33.477 −19.645 1.00 68.15 A C ATOM 2789 C ASP A 363 70.180 32.971 −20.779 1.00 69.51 A C ATOM 2790 O ASP A 363 69.558 33.787 −21.466 1.00 68.87 A O ATOM 2791 CB ASP A 363 71.711 32.343 −18.820 1.00 67.85 A C ATOM 2792 CG ASP A 363 70.722 31.702 −17.869 1.00 67.03 A C ATOM 2793 OD1 ASP A 363 71.157 31.015 −16.923 1.00 67.42 A O ATOM 2794 OD2 ASP A 363 69.490 31.839 −17.981 1.00 67.25 A O ATOM 2795 N GLU A 364 70.111 31.651 −20.981 1.00 71.44 A N ATOM 2796 CA GLU A 364 69.186 31.037 −21.944 1.00 71.30 A C ATOM 2977 C GLU A 364 68.223 30.026 −21.289 1.00 69.20 A C ATOM 2798 O GLU A 364 67.280 29.569 −21.938 1.00 70.14 A O ATOM 2799 CB GLU A 364 69.980 30.351 −23.069 1.00 73.26 A C ATOM 2800 CG GLU A 364 69.968 31.097 −24.399 1.00 74.89 A C ATOM 2801 CD GLU A 364 70.651 32.451 −24.320 1.00 76.70 A C ATOM 2802 OE1 GLU A 364 71.868 32.494 −24.028 1.00 77.66 A O ATOM 2803 OE2 GLU A 364 69.969 33.476 −24.549 1.00 79.09 A O ATOM 2804 N PHE A 365 68.455 29.685 −20.017 1.00 66.67 A N ATOM 2805 CA PHE A 365 67.630 28.704 −19.299 1.00 64.31 A C ATOM 2806 C PHE A 365 66.403 29.347 −18.633 1.00 61.08 A C ATOM 2807 O PHE A 365 65.266 29.082 −19.026 1.00 62.40 A O ATOM 2808 CB PHE A 365 68.464 27.959 −18.245 1.00 65.86 A C ATOM 2809 CG PHE A 365 69.365 26.886 −18.819 1.00 67.96 A C ATOM 2810 CD1 PHE A 365 70.557 27.227 −19.461 1.00 68.71 A C ATOM 2811 CD2 PHE A 365 69.029 25.538 −18.705 1.00 68.02 A C ATOM 2812 CE1 PHE A 365 71.395 26.241 −19.989 1.00 68.45 A C ATOM 2813 CE2 PHE A 365 69.860 24.545 −19.232 1.00 68.28 A C ATOM 2814 CZ PHE A 365 71.045 24.899 −19.874 1.00 68.33 A C ATOM 2815 N ARG A 366 66.636 30.183 −17.624 1.00 54.06 A N ATOM 2816 CA ARG A 366 65.544 30.804 −16.874 1.00 49.84 A C ATOM 2817 C ARG A 366 65.747 32.305 −16.729 1.00 48.18 A C ATOM 2818 O ARG A 366 66.867 32.816 −16.857 1.00 47.96 A O ATOM 2819 CB ARG A 366 65.424 30.159 −15.490 1.00 47.56 A C ATOM 2820 CG ARG A 366 65.240 28.655 −15.525 1.00 43.64 A C ATOM 2821 CD ARG A 366 64.974 28.012 −14.174 1.00 38.98 A C ATOM 2822 NE ARG A 366 66.159 27.987 −13.327 1.00 41.26 A N ATOM 2823 CZ ARG A 366 66.242 27.371 −12.147 1.00 36.86 A C ATOM 2824 NH1 ARG A 366 65.203 26.718 −11.644 1.00 42.11 A N ATOM 2825 NH2 ARG A 366 67.375 27.413 −11.471 1.00 36.33 A N ATOM 2826 N THR A 367 64.654 33.009 −16.446 1.00 46.71 A N ATOM 2827 CA THR A 367 64.675 34.468 −16.397 1.00 46.92 A C ATOM 2828 C THR A 367 63.746 35.043 −15.331 1.00 44.72 A C ATOM 2829 O THR A 367 62.744 34.435 −14.973 1.00 42.54 A O ATOM 2830 CB THR A 367 64.306 35.019 −17.783 1.00 46.57 A C ATOM 2831 OG1 THR A 367 65.143 34.406 −18.774 1.00 49.10 A O ATOM 2832 CG2 THR A 367 64.628 36.484 −17.902 1.00 48.33 A C ATOM 2833 N ALA A 368 64.105 36.219 −14.819 1.00 43.12 A N ATOM 2834 CA ALA A 368 63.206 36.976 −13.962 1.00 37.88 A C ATOM 2835 C ALA A 368 61.990 37.417 −14.772 1.00 31.67 A C ATOM 2836 O ALA A 368 62.091 37.780 −15.946 1.00 33.05 A O ATOM 2837 CB ALA A 368 63.920 38.185 −13.359 1.00 37.36 A C ATOM 2838 N ALA A 369 60.827 37.407 −14.133 1.00 30.27 A N ATOM 2839 CA ALA A 369 59.608 37.776 −14.828 1.00 25.65 A C ATOM 2840 C ALA A 369 58.590 38.454 −13.917 1.00 18.85 A C ATOM 2841 O ALA A 369 58.574 38.264 −12.707 1.00 26.84 A O ATOM 2842 CB ALA A 369 58.988 36.559 −15.484 1.00 26.18 A C ATOM 2843 N VAL A 370 57.772 39.267 −14.543 1.00 21.79 A N ATOM 2844 CA VAL A 370 56.623 39.891 −13.921 1.00 22.63 A C ATOM 2845 C VAL A 370 55.460 39.580 −14.864 1.00 23.34 A C ATOM 2846 O VAL A 370 55.491 39.970 −16.007 1.00 23.37 A O ATOM 2847 CB VAL A 370 56.806 41.403 −13.783 1.00 24.21 A C ATOM 2848 CG1 VAL A 370 55.606 42.016 −13.069 1.00 20.64 A C ATOM 2849 CG2 VAL A 370 58.091 41.738 −13.021 1.00 24.95 A C ATOM 2850 N GLU A 371 54.435 38.890 −14.367 1.00 23.45 A N ATOM 2851 CA GLU A 371 53.364 38.364 −15.208 1.00 26.07 A C ATOM 2852 C GLU A 371 52.005 38.601 −14.556 1.00 21.52 A C ATOM 2853 O GLU A 371 51.886 38.584 −13.346 1.00 22.32 A O ATOM 2854 CB GLU A 371 53.593 36.859 −15.452 1.00 29.04 A C ATOM 2855 CG GLU A 371 54.667 36.583 −16.508 1.00 37.79 A C ATOM 2856 CD GLU A 371 55.383 35.235 −16.373 1.00 42.98 A C ATOM 2857 OE1 GLU A 371 55.957 34.768 −17.389 1.00 47.96 A O ATOM 2858 OE2 GLU A 371 55.428 34.655 −15.271 1.00 46.63 A O ATOM 2859 N GLY A 372 50.997 38.849 −15.375 1.00 23.24 A N ATOM 2860 CA GLY A 372 49.629 38.995 −14.902 1.00 20.28 A C ATOM 2861 C GLY A 372 48.652 39.097 −16.060 1.00 21.84 A C ATOM 2862 O GLY A 372 49.087 39.076 −17.231 1.00 23.46 A O ATOM 2863 N PRO A 373 47.355 39.219 −15.790 1.00 20.69 A N ATOM 2864 CA PRO A 373 46.758 39.117 −14.455 1.00 18.48 A C ATOM 2865 C PRO A 373 46.427 37.686 −14.050 1.00 19.08 A C ATOM 2866 O PRO A 373 46.197 36.821 −14.906 1.00 22.98 A O ATOM 2867 CB PRO A 373 45.466 39.923 −14.607 1.00 20.66 A C ATOM 2868 CG PRO A 373 45.050 39.692 −16.023 1.00 22.14 A C ATOM 2869 CD PRO A 373 46.328 39.516 −16.811 1.00 21.78 A C ATOM 2870 N PHE A 374 46.385 37.445 −12.742 1.00 15.75 A N ATOM 2871 CA PHE A 374 45.882 36.206 −12.195 1.00 16.86 A C ATOM 2872 C PHE A 374 44.622 36.442 −11.376 1.00 21.99 A C ATOM 2873 O PHE A 374 44.370 37.554 −10.943 1.00 19.16 A O ATOM 2874 CB PHE A 374 46.973 35.539 −11.360 1.00 16.65 A C ATOM 2875 CG PHE A 374 48.148 35.118 −12.170 1.00 19.99 A C ATOM 2876 CD1 PHE A 374 48.097 33.957 −12.936 1.00 23.38 A C ATOM 2877 CD2 PHE A 374 49.294 35.894 −12.221 1.00 22.80 A C ATOM 2878 CE1 PHE A 374 49.189 33.565 −13.711 1.00 27.21 A C ATOM 2879 CE2 PHE A 374 50.385 35.503 −12.980 1.00 22.14 A C ATOM 2880 CZ PHE A 374 50.341 34.340 −13.722 1.00 25.11 A C ATOM 2881 N VAL A 375 43.822 35.392 −11.207 1.00 21.84 A N ATOM 2882 CA VAL A 375 42.614 35.458 −10.407 1.00 22.25 A C ATOM 2883 C VAL A 375 42.948 34.876 −9.049 1.00 20.48 A C ATOM 2884 O VAL A 375 43.281 33.695 −8.943 1.00 24.24 A O ATOM 2885 CB VAL A 375 41.439 34.656 −11.016 1.00 24.98 A C ATOM 2886 CG1 VAL A 375 40.206 34.758 −10.119 1.00 22.92 A C ATOM 2887 CG2 VAL A 375 41.117 35.152 −12.404 1.00 23.43 A C ATOM 2888 N THR A 376 42.881 35.710 −8.023 1.00 22.65 A N ATOM 2889 CA THR A 376 43.104 35.291 −6.637 1.00 22.10 A C ATOM 2890 C THR A 376 42.027 35.873 −5.737 1.00 17.23 A C ATOM 2891 O THR A 376 41.856 37.081 −5.647 1.00 20.58 A O ATOM 2892 CB THR A 376 44.490 35.777 −6.137 1.00 23.66 A C ATOM 2893 OG1 THR A 376 45.515 35.417 −7.080 1.00 25.31 A O ATOM 2894 CG2 THR A 376 44.873 35.046 −4.844 1.00 26.58 A C ATOM 2895 N LEU A 377 41.265 35.010 −5.080 1.00 22.23 A N ATOM 2896 CA LEU A 377 40.199 35.472 −4.205 1.00 23.50 A C ATOM 2897 C LEU A 377 40.708 35.632 −2.776 1.00 27.50 A C ATOM 2898 O LEU A 377 41.710 35.019 −2.401 1.00 28.12 A O ATOM 2899 CB LEU A 377 39.046 34.481 −4.217 1.00 26.48 A C ATOM 2900 CG LEU A 377 38.541 34.109 −5.622 1.00 29.26 A C ATOM 2901 CD1 LEU A 377 37.314 33.287 −5.496 1.00 30.60 A C ATOM 2902 CD2 LEU A 377 38.247 35.344 −6.466 1.00 29.52 A C ATOM 2903 N ASP A 378 39.981 36.441 −2.014 1.00 29.13 A N ATOM 2904 CA ASP A 378 40.177 36.631 −0.574 1.00 35.27 A C ATOM 2905 C ASP A 378 41.540 37.210 −0.251 1.00 33.60 A C ATOM 2906 O ASP A 378 42.134 36.858 0.760 1.00 36.99 A O ATOM 2907 CB ASP A 378 40.002 35.325 0.196 1.00 33.08 A C ATOM 2908 CG ASP A 378 38.627 34.762 0.070 1.00 36.04 A C ATOM 2909 OD1 ASP A 378 37.654 35.549 −0.049 1.00 31.19 A O ATOM 2910 OD2 ASP A 378 38.441 33.532 0.097 1.00 41.39 A O ATOM 2911 N MET A 379 42.026 38.096 −1.110 1.00 34.47 A N ATOM 2912 CA MET A 379 43.349 38.682 −0.933 1.00 33.96 A C ATOM 2913 C MET A 379 43.396 39.613 0.270 1.00 34.59 A C ATOM 2914 O MET A 379 44.449 39.755 0.871 1.00 37.56 A O ATOM 2915 CB MET A 379 43.782 39.449 −2.186 1.00 30.92 A C ATOM 2916 CG MET A 379 44.041 38.562 −3.375 1.00 28.94 A C ATOM 2917 SD MET A 379 44.749 39.489 −4.761 1.00 26.10 A S ATOM 2918 CE MET A 379 43.486 40.462 −5.207 1.00 25.48 A C ATOM 2919 N GLU A 380 42.268 40.233 0.615 1.00 41.66 A N ATOM 2920 CA GLU A 380 42.182 41.091 1.805 1.00 46.13 A C ATOM 2921 C GLU A 380 42.498 40.308 3.080 1.00 47.68 A C ATOM 2922 O GLU A 380 43.208 40.810 3.957 1.00 50.01 A O ATOM 2923 CB GLU A 380 40.803 41.741 1.927 1.00 48.86 A C ATOM 2924 CG GLU A 380 40.743 43.189 1.446 1.00 51.99 A C ATOM 2925 CD GLU A 380 40.851 43.338 −0.066 1.00 55.58 A C ATOM 2926 OE1 GLU A 380 40.498 42.385 −0.799 1.00 56.65 A O ATOM 2927 OE2 GLU A 380 41.282 44.426 −0.524 1.00 57.63 A O ATOM 2928 N ASP A 381 41.997 39.075 3.169 1.00 46.10 A N ATOM 2929 CA ASP A 381 42.296 38.192 4.309 1.00 46.90 A C ATOM 2930 C ASP A 381 43.774 37.804 4.428 1.00 44.71 A C ATOM 2931 O ASP A 381 44.167 37.175 5.402 1.00 45.68 A O ATOM 2932 CB ASP A 381 41.448 36.911 4.254 1.00 45.21 A C ATOM 2933 CG ASP A 381 40.052 37.059 3.994 0.00 50.29 A C ATOM 2934 OD1 ASP A 381 39.485 37.731 4.881 0.00 50.63 A O ATOM 2935 OD2 ASP A 381 39.440 36.553 3.030 0.00 50.70 A O ATOM 2936 N CYS A 382 44.587 38.137 3.429 1.00 43.03 A N ATOM 2937 CA CYS A 382 46.026 37.939 3.526 1.00 42.15 A C ATOM 2938 C CYS A 382 46.693 39.021 4.400 1.00 41.50 A C ATOM 2939 O CYS A 382 47.808 38.827 4.855 1.00 43.47 A O ATOM 2940 CB CYS A 382 46.669 37.897 2.137 1.00 41.83 A C ATOM 2941 SG CYS A 382 45.985 36.643 1.026 1.00 38.22 A S ATOM 2942 N GLY A 383 45.999 40.133 4.645 1.00 43.76 A N ATOM 2943 CA GLY A 383 46.521 41.233 5.447 1.00 47.67 A C ATOM 2944 C GLY A 383 46.200 41.165 6.939 1.00 51.51 A C ATOM 2945 O GLY A 383 45.034 41.086 7.329 1.00 52.22 A O ATOM 2946 N TYR A 384 47.239 41.220 7.772 1.00 55.14 A N ATOM 2947 CA TYR A 384 47.092 41.146 9.227 1.00 57.40 A C ATOM 2948 C TYR A 384 46.613 42.453 9.878 1.00 58.55 A C ATOM 2949 O TYR A 384 47.216 43.508 9.687 1.00 56.79 A O ATOM 2950 CB TYR A 384 48.414 40.719 9.865 1.00 57.72 A C ATOM 2951 CG TYR A 384 48.357 40.643 11.375 1.00 60.49 A C ATOM 2952 CD1 TYR A 384 47.657 39.623 12.015 1.00 61.73 A C ATOM 2953 CD2 TYR A 384 48.994 41.598 12.167 1.00 62.68 A C ATOM 2954 CE1 TYR A 384 47.597 39.551 13.408 1.00 61.50 A C ATOM 2955 CE2 TYR A 384 48.941 41.536 13.561 1.00 62.87 A C ATOM 2956 CZ TYR A 384 48.242 40.510 14.173 1.00 62.60 A C ATOM 2957 OH TYR A 384 48.188 40.443 15.548 1.00 62.41 A O ATOM 2958 N ASN A 385 45.540 42.359 10.666 1.00 60.14 A N ATOM 2959 CA ASN A 385 45.049 43.478 11.471 1.00 62.13 A C ATOM 2960 C ASN A 385 45.450 43.295 12.938 1.00 63.14 A C ATOM 2961 1OCT ASN A 385 46.043 44.168 13.582 1.00 64.31 A O ATOM 2962 CB ASN A 385 43.524 43.592 11.362 1.00 62.36 A C ATOM 2963 CG ASN A 385 43.037 43.666 9.918 1.00 63.95 A C ATOM 2964 OD1 ASN A 385 42.654 42.654 9.326 1.00 64.71 A O ATOM 2965 ND2 ASN A 385 43.043 44.866 9.351 1.00 63.38 A N ATOM 2966 2OCT ASN A 385 45.193 42.257 13.550 1.00 63.30 A O ATOM 2967 O HOH W 1 79.629 68.206 12.595 1.00 19.21 W O ATOM 2968 O HOH W 2 49.015 47.109 −12.447 1.00 16.55 W O ATOM 2969 O HOH W 3 85.976 52.179 5.603 1.00 21.59 W O ATOM 2970 O HOH W 4 80.248 66.497 15.419 1.00 25.04 W O ATOM 2971 O HOH W 5 75.516 59.444 −7.006 1.00 20.45 W O ATOM 2972 O HOH W 6 64.679 60.731 5.508 1.00 20.67 W O ATOM 2973 O HOH W 7 52.200 57.481 −0.615 1.00 36.49 W O ATOM 2974 O HOH W 8 52.125 39.097 −18.355 1.00 30.59 W O ATOM 2975 O HOH W 9 66.983 62.454 10.671 1.00 21.40 W O ATOM 2976 O HOH W 10 44.515 33.044 −12.767 1.00 22.53 W O ATOM 2977 O HOH W 11 80.173 73.603 4.481 1.00 33.04 W O ATOM 2978 O HOH W 12 47.807 50.724 −13.972 1.00 20.13 W O ATOM 2979 O HOH W 13 80.860 59.315 0.203 1.00 26.62 W O ATOM 2980 O HOH W 14 55.473 70.139 −4.604 1.00 53.88 W O ATOM 2981 O HOH W 15 74.472 71.225 −0.260 1.00 39.12 W O ATOM 2982 O HOH W 16 40.544 39.218 −3.509 1.00 31.61 W O ATOM 2983 O HOH W 17 80.450 59.844 12.764 1.00 26.37 W O ATOM 2984 O HOH W 18 66.075 77.514 3.855 1.00 38.59 W O ATOM 2985 O HOH W 19 85.138 68.322 12.518 1.00 27.81 W O ATOM 2986 O HOH W 20 87.998 70.949 7.571 1.00 53.38 W O ATOM 2987 O HOH W 21 87.495 66.754 13.176 1.00 21.08 W O ATOM 2988 O HOH W 22 49.756 30.124 −1.047 1.00 45.82 W O ATOM 2989 O HOH W 23 49.361 33.536 13.751 1.00 66.10 W O ATOM 2990 O HOH W 24 67.788 54.838 10.862 1.00 28.51 W O ATOM 2991 O HOH W 25 50.160 45.140 −1.881 1.00 27.20 W O ATOM 2992 O HOH W 26 82.766 67.175 5.119 1.00 34.54 W O ATOM 2993 O HOH W 27 45.592 32.973 −7.823 1.00 33.43 W O ATOM 2994 O HOH W 28 81.090 55.720 18.331 1.00 22.44 W O ATOM 2995 O HOH W 29 43.057 33.861 0.341 1.00 80.20 W O ATOM 2996 O HOH W 30 61.780 27.615 13.286 1.00 58.09 W O ATOM 2997 O HOH W 31 50.466 45.953 8.884 1.00 40.45 W O ATOM 2998 O HOH W 32 83.327 58.106 0.741 1.00 25.84 W O ATOM 2999 O HOH W 33 81.327 48.709 18.206 1.00 36.23 W O ATOM 3000 O HOH W 34 72.944 38.241 4.000 1.00 50.15 W O ATOM 3001 O HOH W 35 48.453 40.727 −19.960 1.00 41.17 W O ATOM 3002 O HOH W 36 66.664 48.548 5.951 1.00 33.26 W O ATOM 3003 O HOH W 37 58.083 43.778 −17.062 1.00 24.83 W O ATOM 3004 O HOH W 38 55.799 60.814 5.110 1.00 39.72 W O ATOM 3005 O HOH W 39 79.293 52.119 13.860 1.00 21.39 W O ATOM 3006 O HOH W 40 77.511 45.900 20.280 1.00 50.24 W O ATOM 3007 O HOH W 41 50.802 43.439 −20.117 1.00 42.67 W O ATOM 3008 O HOH W 42 66.106 19.960 −9.172 1.00 47.01 W O ATOM 3009 O HOH W 43 63.894 58.910 −19.204 1.00 76.51 W O ATOM 3010 O HOH W 44 76.257 41.684 15.651 1.00 62.92 W O ATOM 3011 O HOH W 45 54.819 50.279 −18.015 1.00 21.51 W O ATOM 3012 O HOH W 46 65.401 64.403 6.138 1.00 24.60 W O ATOM 3013 O HOH W 47 53.853 55.150 −11.636 1.00 29.65 W O ATOM 3014 O HOH W 48 68.908 67.519 −5.703 1.00 33.79 W O ATOM 3015 O HOH W 49 79.968 52.673 6.743 1.00 26.80 W O ATOM 3016 O HOH W 50 48.181 44.979 −10.637 1.00 17.31 W O ATOM 3017 O HOH W 51 53.488 60.669 −0.029 1.00 31.52 W O ATOM 3018 O HOH W 52 62.724 61.887 9.306 1.00 24.34 W O ATOM 3019 O HOH W 53 64.870 59.282 19.837 1.00 40.43 W O ATOM 3020 O HOH W 54 67.034 55.997 8.478 1.00 18.91 W O ATOM 3021 O HOH W 55 81.783 69.009 13.884 1.00 24.02 W O ATOM 3022 O HOH W 56 62.338 60.129 2.848 1.00 20.26 W O ATOM 3023 O HOH W 57 59.948 49.626 3.509 1.00 20.58 W O ATOM 3024 O HOH W 58 74.315 61.973 −6.807 1.00 24.90 W O ATOM 3025 O HOH W 59 72.754 44.483 0.023 1.00 30.57 W O ATOM 3026 O HOH W 60 85.756 65.674 6.462 1.00 34.66 W O ATOM 3027 O HOH W 61 65.197 62.897 8.395 1.00 24.15 W O ATOM 3028 O HOH W 62 83.185 55.955 4.621 1.00 21.13 W O ATOM 3029 O HOH W 63 68.666 31.435 6.797 1.00 32.75 W O ATOM 3030 O HOH W 64 70.959 50.115 −0.021 1.00 24.74 W O ATOM 3031 O HOH W 65 70.634 69.168 18.081 1.00 35.02 W O ATOM 3032 O HOH W 66 83.133 65.815 2.329 1.00 28.15 W O ATOM 3033 O HOH W 67 81.369 47.920 15.072 1.00 41.54 W O ATOM 3034 O HOH W 68 87.299 59.567 9.845 1.00 38.69 W O ATOM 3035 O HOH W 69 41.854 32.167 −5.319 1.00 34.05 W O ATOM 3036 O HOH W 70 87.742 64.125 6.529 1.00 68.19 W O ATOM 3037 O HOH W 71 72.460 68.092 12.019 1.00 27.07 W O ATOM 3038 O HOH W 72 65.274 42.384 −19.635 1.00 61.51 W O ATOM 3039 O HOH W 73 85.768 65.313 2.708 1.00 45.28 W O ATOM 3040 O HOH W 74 62.071 26.325 −12.323 1.00 30.75 W O ATOM 3041 O HOH W 75 53.548 58.246 7.753 1.00 35.77 W O ATOM 3042 O HOH W 76 48.415 35.384 −17.283 1.00 49.88 W O ATOM 3043 O HOH W 77 63.389 66.452 6.071 1.00 24.26 W O ATOM 3044 O HOH W 78 82.811 58.045 −3.976 1.00 49.01 W O ATOM 3045 O HOH W 79 73.849 44.456 −1.977 1.00 46.53 W O ATOM 3046 O HOH W 80 45.102 52.297 −10.384 1.00 27.65 W O ATOM 3047 O HOH W 81 65.497 47.590 −7.949 1.00 22.50 W O ATOM 3048 O HOH W 82 60.385 50.571 −20.969 1.00 35.94 W O ATOM 3049 O HOH W 83 73.977 51.153 −13.532 1.00 42.34 W O ATOM 3050 O HOH W 84 73.807 75.017 −0.696 1.00 45.17 W O ATOM 3051 O HOH W 85 89.302 56.875 9.021 1.00 36.01 W O ATOM 3052 O HOH W 86 59.573 59.896 2.947 1.00 37.55 W O ATOM 3053 O HOH W 87 69.343 40.980 6.123 1.00 33.99 W O ATOM 3054 O HOH W 88 52.716 58.960 −10.022 1.00 38.62 W O ATOM 3055 O HOH W 89 71.368 68.265 20.363 1.00 40.93 W O ATOM 3056 O HOH W 90 58.025 24.259 10.874 1.00 64.35 W O ATOM 3057 O HOH W 91 79.324 57.854 −5.249 1.00 28.34 W O ATOM 3058 O HOH W 92 52.049 42.888 4.777 1.00 33.22 W O ATOM 3059 O HOH W 93 58.572 51.240 −21.845 1.00 39.18 W O ATOM 3060 O HOH W 94 58.399 59.801 −15.372 1.00 34.06 W O ATOM 3061 O HOH W 95 51.199 63.163 −3.700 1.00 34.26 W O ATOM 3062 O HOH W 96 39.751 42.093 5.333 1.00 63.63 W O ATOM 3063 O HOH W 97 62.377 69.523 12.319 1.00 37.67 W O ATOM 3064 O HOH W 98 57.972 57.007 14.799 1.00 35.19 W O ATOM 3065 O HOH W 99 62.896 33.477 −11.943 1.00 76.49 W O ATOM 3066 O HOH W 100 77.078 56.466 −5.817 1.00 21.61 W O ATOM 3067 O HOH W 101 58.723 72.174 10.770 1.00 45.78 W O ATOM 3068 O HOH W 102 82.563 53.786 6.291 1.08 28.84 W O ATOM 3069 O HOH W 103 59.353 71.034 3.910 1.00 33.97 W O ATOM 3070 O HOH W 104 64.748 30.333 −21.491 1.00 39.71 W O ATOM 3071 O HOH W 105 74.634 59.328 −12.866 1.00 40.33 W O ATOM 3072 O HOH W 106 55.438 42.543 −19.877 1.00 35.74 W O ATOM 3073 O HOH W 107 77.532 77.780 −0.830 1.00 47.95 W O ATOM 3074 O HOH W 108 65.148 68.989 −11.545 1.00 51.49 W O ATOM 3075 O HOH W 109 57.778 41.274 −18.333 1.00 41.55 W O ATOM 3076 O HOH W 110 55.086 59.049 16.334 1.00 47.49 W O ATOM 3077 O HOH W 111 81.228 50.040 13.406 1.00 68.55 W O ATOM 3078 O HOH W 112 39.213 39.599 −0.284 1.00 54.99 W O ATOM 3079 O HOH W 113 58.054 38.933 −17.692 1.00 30.12 W O ATOM 3080 O HOH W 114 46.682 50.824 −7.093 1.00 27.96 W O ATOM 3081 O HOH W 115 56.111 63.217 −0.389 1.00 31.05 W O ATOM 3082 O HOH W 116 83.364 67.774 0.538 1.00 32.16 W O ATOM 3083 O HOH W 117 48.343 27.854 7.458 1.00 45.35 W O ATOM 3084 O HOH W 118 62.036 71.098 6.922 1.00 37.49 W O ATOM 3085 O HOH W 119 50.470 55.859 8.484 1.00 50.28 W O ATOM 3086 O HOH W 120 59.219 48.282 −21.628 1.00 49.61 W O ATOM 3087 O HOH W 121 70.795 46.171 0.982 1.00 42.89 W O ATOM 3088 O HOH W 122 67.725 50.769 8.365 1.00 44.67 W O ATOM 3089 O HOH W 123 62.717 69.639 −10.878 1.00 52.07 W O ATOM 3090 O HOH W 124 60.253 41.588 −20.165 1.00 31.75 W O ATOM 3091 O HOH W 125 40.595 48.954 −7.729 1.00 24.22 W O ATOM 3092 O HOH W 126 60.544 37.484 −18.077 1.00 33.87 W O ATOM 3093 O HOH W 127 65.662 55.956 21.772 1.00 33.55 W O ATOM 3094 O HOH W 128 65.944 31.897 −19.969 1.00 51.23 W O ATOM 3095 O HOH W 129 61.793 76.127 1.749 1.00 56.51 W O ATOM 3096 O HOH W 130 85.302 59.460 0.012 1.00 36.81 W O ATOM 3097 O HOH W 131 51.594 64.021 −6.048 1.00 58.01 W O ATOM 3098 O HOH W 132 54.042 66.667 −6.161 1.00 63.77 W O ATOM 3099 O HOH W 133 62.332 75.297 4.414 1.00 55.75 W O ATOM 3100 O HOH W 134 50.042 46.059 −20.292 1.00 73.57 W O ATOM 3101 O HOH W 135 79.366 53.491 −11.459 1.00 45.91 W O ATOM 3102 O HOH W 136 62.077 57.368 −20.403 1.00 50.99 W O ATOM 3103 O HOH W 137 70.534 49.754 8.111 1.00 67.69 W O ATOM 3104 O HOH W 138 78.803 66.881 19.280 1.00 33.48 W O ATOM 3105 O HOH W 139 83.041 34.659 −5.519 1.00 42.03 W O ATOM 3106 O HOH W 140 77.602 56.674 −9.068 1.00 43.32 W O ATOM 3107 O HOH W 141 80.073 75.620 15.238 1.00 30.64 W O ATOM 3108 O HOH W 142 80.099 63.907 −8.340 1.00 39.92 W O ATOM 3109 O HOH W 143 56.033 68.239 −6.044 1.00 52.71 W O ATOM 3110 O HOH W 144 53.413 63.896 −8.009 1.00 35.96 W O ATOM 3111 O HOH W 145 89.147 64.107 9.192 1.00 45.54 W O ATOM 3112 O HOH W 146 37.356 37.399 −3.003 1.00 37.40 W O ATOM 3113 O HOH W 147 71.841 68.945 −7.695 1.00 67.24 W O ATOM 3114 O HOH W 148 65.710 25.459 1.815 1.00 68.03 W O ATOM 3115 O HOH W 149 54.563 32.460 14.878 1.00 45.89 W O ATOM 3116 O HOH W 150 69.771 32.591 −13.970 1.00 38.39 W O ATOM 3117 O HOH W 151 40.372 41.672 −3.643 1.00 35.36 W O ATOM 3118 O HOH W 152 67.233 45.846 −10.950 1.00 26.82 W O ATOM 3119 O HOH W 153 38.766 47.051 −8.023 1.00 28.56 W O ATOM 3120 O HOH W 154 81.319 69.504 −2.622 1.00 45.91 W O ATOM 3121 O HOH W 155 53.761 29.575 −15.833 1.00 38.29 W O ATOM 3122 O HOH W 156 56.342 73.135 −5.405 1.00 68.20 W O ATOM 3123 O HOH W 157 53.773 72.306 −0.902 1.00 67.09 W O ATOM 3124 O HOH W 158 79.692 66.676 −5.072 1.00 50.12 W O ATOM 3125 O HOH W 159 73.232 38.089 −7.677 1.00 45.17 W O ATOM 3126 O HOH W 160 46.657 52.288 −3.310 1.00 36.02 W O ATOM 3127 O HOH W 161 68.327 19.772 −0.212 1.00 70.84 W O ATOM 3128 O HOH W 162 57.706 29.223 −8.479 1.00 39.36 W O ATOM 3129 O HOH W 163 80.380 78.795 5.802 1.00 56.31 W O ATOM 3130 O HOH W 164 56.675 59.728 −19.716 1.00 51.35 W O ATOM 3131 O HOH W 165 72.021 78.865 10.956 1.00 57.63 W O ATOM 3132 O HOH W 166 61.187 22.723 11.672 1.00 52.43 W O ATOM 3133 O HOH W 167 52.637 65.982 −3.596 1.00 43.55 W O ATOM 3134 O HOH W 168 77.094 59.049 −11.764 1.00 53.68 W O ATOM 3135 O HOH W 169 82.297 55.117 −5.408 1.00 56.75 W O ATOM 3136 O HOH W 170 44.896 54.140 −2.621 1.00 44.26 W O ATOM 3137 O HOH W 171 75.662 48.265 9.068 1.00 31.34 W O ATOM 3138 O HOH W 172 62.322 26.608 −15.255 1.00 73.50 W O ATOM 3139 O HOH W 173 70.503 79.530 7.957 1.00 46.42 W O ATOM 3140 O HOH W 174 78.756 79.738 3.636 1.00 57.59 W O ATOM 3141 O HOH W 175 63.567 48.079 7.690 1.00 56.49 W O ATOM 3142 O HOH W 176 73.105 50.182 8.251 1.00 62.98 W O ATOM 3143 O HOH W 177 74.155 72.309 −2.546 1.00 63.14 W O ATOM 3144 O HOH W 178 65.269 74.588 10.615 1.00 38.50 W O ATOM 3145 O HOH W 179 77.404 52.712 −10.561 1.00 40.86 W O ATOM 3146 O HOH W 180 53.494 69.486 −1.573 1.00 61.27 W O ATOM 3147 O HOH W 181 44.408 43.630 15.946 1.00 63.55 W O ATOM 3148 O HOH W 182 45.148 46.355 9.428 1.00 58.76 W O ATOM 3149 O HOH W 183 78.021 49.570 −0.246 1.00 32.19 W O ATOM 3150 O HOH W 184 81.804 50.829 −2.607 1.00 38.10 W O ATOM 3151 O HOH W 185 88.410 73.240 7.564 1.00 56.30 W O ATOM 3152 O HOH W 186 61.080 66.476 15.948 1.00 68.96 W O ATOM 3153 O HOH W 187 45.110 31.905 1.445 1.00 67.43 W O ATOM 3154 O HOH W 188 49.200 55.926 12.964 1.00 72.28 W O ATOM 3155 O HOH W 189 71.187 76.958 15.269 1.00 39.87 W O ATOM 3156 O HOH W 190 73.886 47.482 4.081 1.00 53.55 W O ATOM 3157 O HOH W 191 69.355 68.996 −15.162 1.00 61.52 W O ATOM 3158 O HOH W 192 82.777 65.787 −8.682 1.00 62.77 W O ATOM 3159 O HOH W 193 39.736 46.583 7.480 1.00 62.23 W O ATOM 3160 O HOH W 194 52.055 40.044 −22.266 1.00 55.63 W O ATOM 3161 O HOH W 195 71.314 50.785 −16.556 1.00 49.70 W O ATOM 3162 O HOH W 196 61.950 38.755 −19.713 1.00 70.81 W O ATOM 3163 O HOH W 197 84.051 69.275 5.460 1.00 48.64 W O ATOM 3164 O HOH W 198 76.032 60.681 20.880 1.00 69.12 W O ATOM 3165 O HOH W 199 73.266 44.918 4.326 1.00 68.75 W O ATOM 3166 O HOH W 200 82.129 50.468 −5.451 1.00 59.02 W O ATOM 3167 O HOH W 201 83.221 72.917 3.600 1.00 40.04 W O ATOM 3168 O HOH W 202 59.652 75.257 4.275 1.00 57.30 W O ATOM 3169 O HOH W 203 78.123 47.635 22.706 1.00 45.73 W O ATOM 3170 O HOH W 204 77.637 76.375 11.568 1.00 43.51 W O ATOM 3171 O HOH W 205 58.555 48.938 13.305 1.00 48.92 W O ATOM 3172 O HOH W 206 57.638 66.927 18.153 1.00 50.79 W O ATOM 3173 O HOH W 207 58.312 43.498 7.697 1.00 33.77 W O ATOM 3174 O HOH W 208 44.538 28.297 3.536 1.00 55.65 W O ATOM 3175 O HOH W 209 59.595 53.833 19.308 1.00 58.04 W O ATOM 3176 O HOH W 210 57.084 51.317 14.707 1.00 51.78 W O ATOM 3177 O HOH W 211 49.436 21.830 −1.938 1.00 62.41 W O ATOM 3178 O HOH W 212 60.734 77.657 4.018 1.00 73.34 W O ATOM 3179 O HOH W 213 79.123 83.308 3.898 1.00 63.20 W O ATOM 3180 O HOH W 214 57.523 61.921 −13.519 1.00 37.25 W O ATOM 3181 O HOH W 215 71.168 43.072 5.167 1.00 41.82 W O ATOM 3182 O HOH W 216 76.653 84.242 3.301 1.00 78.23 W O ATOM 3183 O HOH W 217 42.382 40.135 17.622 1.00 61.51 W O ATOM 3184 O HOH W 218 78.733 69.517 −5.343 1.00 61.81 W O ATOM 3185 O HOH W 219 62.986 22.749 −4.555 1.00 42.82 W O ATOM 3186 O HOH W 220 60.743 44.247 9.220 1.00 48.58 W O ATOM 3187 O HOH W 221 57.413 29.275 −13.554 1.00 41.77 W O ATOM 3188 O HOH W 222 71.784 39.808 −3.358 1.00 49.72 W O ATOM 3189 O HOH W 223 74.571 63.700 −13.618 1.00 53.93 W O ATOM 3190 O HOH W 224 71.261 51.431 −13.741 1.00 41.48 W O ATOM 3191 O HOH W 225 78.559 79.217 0.998 1.00 50.39 W O ATOM 3192 O HOH W 226 68.431 42.241 17.534 1.00 51.33 W O ATOM 3193 O HOH W 227 74.858 56.378 23.475 1.00 62.51 W O ATOM 3194 O HOH W 228 79.307 60.745 22.219 1.00 40.98 W O ATOM 3195 O HOH W 229 60.314 68.573 10.249 1.00 29.74 W O ATOM 3196 O HOH W 230 61.602 71.621 −9.518 1.00 51.81 W O ATOM 3197 O HOH W 231 49.899 42.585 7.057 1.00 35.46 W O ATOM 3198 O HOH W 232 46.590 57.769 2.535 1.00 69.32 W O ATOM 3199 O HOH W 233 45.044 34.173 −1.541 1.00 50.34 W O ATOM 3200 O HOH W 234 71.447 46.668 −18.182 1.00 58.66 W O ATOM 3201 O HOH W 235 73.000 43.214 −18.003 1.00 45.06 W O ATOM 3202 O HOH W 236 43.370 55.663 −1.011 1.00 61.60 W O ATOM 3203 O HOH W 237 74.007 57.458 −17.330 1.00 59.05 W O ATOM 3204 O HOH W 238 78.277 52.906 −16.612 1.00 65.63 W O ATOM 3205 O HOH W 239 77.796 59.191 −8.755 1.00 45.94 W O ATOM 3206 O HOH W 240 84.436 60.164 −3.135 1.00 53.03 W O ATOM 3207 O HOH W 241 65.112 49.259 9.447 1.00 53.21 W O ATOM 3208 O HOH W 242 63.207 51.425 10.118 1.00 42.58 W O ATOM 3209 O HOH W 243 89.242 51.621 10.559 1.00 37.79 W O ATOM 3210 O HOH W 244 88.861 58.033 −1.500 1.00 63.56 W O ATOM 3211 O HOH W 245 80.840 77.800 12.517 1.00 43.88 W O ATOM 3212 O HOH W 246 77.216 83.653 0.754 1.00 66.92 W O ATOM 3213 O HOH W 247 69.579 67.222 23.238 1.00 67.75 W O ATOM 3214 O HOH W 248 75.887 51.320 21.816 1.00 72.66 W O ATOM 3215 O HOH W 249 68.191 78.916 4.291 1.00 52.82 W O ATOM 3216 O HOH W 250 82.004 63.181 21.579 1.00 30.60 W O ATOM 3217 O HOH W 251 76.390 67.886 21.910 1.00 51.17 W O ATOM 3218 O HOH W 252 53.503 60.921 17.416 1.00 72.58 W O ATOM 3219 O HOH W 253 60.509 46.370 −23.693 1.00 62.40 W O ATOM 3220 O HOH W 254 53.842 41.622 −18.205 1.00 43.31 W O ATOM 3221 O HOH W 255 48.037 45.876 −0.170 1.00 42.34 W O ATOM 3222 O HOH W 256 44.592 45.050 2.573 1.00 46.37 W O ATOM 3223 O HOH W 257 40.130 44.608 4.624 1.00 61.11 W O ATOM 3224 O HOH W 258 69.355 47.143 5.898 1.00 60.82 W O ATOM 3225 O HOH W 259 34.957 32.570 1.397 1.00 47.77 W O ATOM 3226 O HOH W 260 61.555 31.492 −14.640 1.00 63.05 W O ATOM 3227 O HOH W 261 43.862 53.451 −5.566 1.00 71.67 W O ATOM 3228 O HOH W 262 84.234 48.309 0.364 1.00 54.03 W O ATOM 3229 O HOH W 263 87.932 51.816 −3.215 1.00 57.80 W O ATOM 3230 O HOH W 264 82.425 63.456 −6.283 1.00 62.42 W O ATOM 3231 O HOH W 265 80.271 28.172 9.463 1.00 40.70 W O ATOM 3232 O HOH W 266 73.963 30.020 4.302 1.00 26.30 W O ATOM 3233 O HOH W 267 83.112 71.680 1.066 1.00 51.04 W O ATOM 3234 O HOH W 268 63.047 54.124 10.355 1.00 50.34 W O ATOM 3235 O HOH W 269 83.682 62.329 −4.165 1.00 42.75 W O ATOM 3236 O HOH W 270 61.547 73.522 −7.931 1.00 47.36 W O ATOM 3237 O HOH W 271 60.577 53.517 13.966 1.00 53.55 W O ATOM 3238 O HOH W 272 54.580 71.014 −6.905 1.00 46.69 W O ATOM 3239 O HOH W 273 77.926 39.031 −0.508 1.00 49.59 W O ATOM 3240 O HOH W 274 69.669 49.137 −17.891 1.00 45.33 W O ATOM 3241 O HOH W 275 44.777 49.840 1.964 1.00 44.62 W O ATOM 3242 O HOH W 276 48.453 54.600 5.308 1.00 39.43 W O ATOM 3243 O HOH W 277 51.764 32.262 13.155 1.00 71.42 W O ATOM 3244 O HOH W 278 60.951 29.296 11.161 1.00 53.99 W O ATOM 3245 O HOH W 279 68.206 23.452 8.777 1.00 50.70 W O ATOM 3246 O HOH W 280 87.567 24.412 −10.981 1.00 49.42 W O ATOM 3247 O HOH W 281 81.650 24.690 −15.233 1.00 46.79 W O ATOM 3248 O HOH W 282 83.121 29.023 −15.678 1.00 59.22 W O ATOM 3249 O HOH W 283 81.854 31.654 −13.384 1.00 44.68 W O ATOM 3250 O HOH W 284 43.424 43.922 −5.261 1.00 38.18 W O ATOM 3251 O HOH W 285 80.484 32.987 −6.395 1.00 39.87 W O ATOM 3252 I IOD J 1 80.243 57.842 15.501 0.75 23.63 J I ATOM 3253 I IOD J 2 81.546 50.334 15.785 0.50 35.87 J I ATOM 3254 I IOD J 3 51.528 57.888 −13.233 0.50 56.82 J I END

[0511]

1 46 1 1368 DNA Homo sapiens 1 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg ccggaggggc 180 agctttgtgg agatggtgga caacctgagg ggcaagtcgg ggcagggcta ctacgtggag 240 atgaccgtgg gcagcccccc gcagacgctc aacatcctgg tggatacagg cagcagtaac 300 tttgcagtgg gtgctgcccc ccaccccttc ctgcatcgct actaccagag gcagctgtcc 360 agcacatacc gggacctccg gaagggtgtg tatgtgccct acacccaggg caagtgggaa 420 ggggagctgg gcaccgacct ggtaagcatc ccccatggcc ccaacgtcac tgtgcgtgcc 480 aacattgctg ccatcactga atcagacaag ttcttcatca acggctccaa ctgggaaggc 540 atcctggggc tggcctatgc tgagattgcc aggcctgacg actccctgga gcctttcttt 600 gactctctgg taaagcagac ccacgttccc aacctcttct ccctgcagct ttgtggtgct 660 ggcttccccc tcaaccagtc tgaagtgctg gcctctgtcg gagggagcat gatcattgga 720 ggtatcgacc actcgctgta cacaggcagt ctctggtata cacccatccg gcgggagtgg 780 tattatgagg tgatcattgt gcgggtggag atcaatggac aggatctgaa aatggactgc 840 aaggagtaca actatgacaa gagcattgtg gacagtggca ccaccaacct tcgtttgccc 900 aagaaagtgt ttgaagctgc agtcaaatcc atcaaggcag cctcctccac ggagaagttc 960 cctgatggtt tctggctagg agagcagctg gtgtgctggc aagcaggcac caccccttgg 1020 aacattttcc cagtcatctc actctaccta atgggtgagg ttaccaacca gtccttccgc 1080 atcaccatcc ttccgcagca atacctgcgg ccagtggaag atgtggccac gtcccaagac 1140 gactgttaca agtttgccat ctcacagtca tccacgggca ctgttatggg agctgttatc 1200 atggagggct tctacgttgt ctttgatcgg gcccgaaaac gaattggctt tgctgtcagc 1260 gcttgccatg tgcacgatga gttcaggacg gcagcggtgg aaggcccttt tgtcaccttg 1320 gacatggaag actgtggcta caacattcca cagacagatg agtcataa 1368 2 455 PRT Homo sapiens 2 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Arg Arg Gly Ser Phe Val Glu 50 55 60 Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu 65 70 75 80 Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr 85 90 95 Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His 100 105 110 Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys 115 120 125 Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly 130 135 140 Thr Asp Leu Val Ser Ile Pro His Gly Pro Asn Val Thr Val Arg Ala 145 150 155 160 Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Asn Gly Ser 165 170 175 Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro 180 185 190 Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His 195 200 205 Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu 210 215 220 Asn Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly 225 230 235 240 Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile 245 250 255 Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn 260 265 270 Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser 275 280 285 Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe 290 295 300 Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe 305 310 315 320 Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly 325 330 335 Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly 340 345 350 Glu Val Thr Asn Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr 355 360 365 Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys 370 375 380 Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile 385 390 395 400 Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly 405 410 415 Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala 420 425 430 Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn 435 440 445 Ile Pro Gln Thr Asp Glu Ser 450 455 3 1386 DNA Homo sapiens 3 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg ccggaggggc 180 agctttgtgg agatggtgga caacctgagg ggcaagtcgg ggcagggcta ctacgtggag 240 atgaccgtgg gcagcccccc gcagacgctc aacatcctgg tggatacagg cagcagtaac 300 tttgcagtgg gtgctgcccc ccaccccttc ctgcatcgct actaccagag gcagctgtcc 360 agcacatacc gggacctccg gaagggtgtg tatgtgccct acacccaggg caagtgggaa 420 ggggagctgg gcaccgacct ggtaagcatc ccccatggcc cccaggtcac tgtgcgtgcc 480 aacattgctg ccatcactga atcagacaag ttcttcatcc agggctccaa ctgggaaggc 540 atcctggggc tggcctatgc tgagattgcc aggcctgacg actccctgga gcctttcttt 600 gactctctgg taaagcagac ccacgttccc aacctcttct ccctgcagct ttgtggtgct 660 ggcttccccc tccagcagtc tgaagtgctg gcctctgtcg gagggagcat gatcattgga 720 ggtatcgacc actcgctgta cacaggcagt ctctggtata cacccatccg gcgggagtgg 780 tattatgagg tgatcattgt gcgggtggag atcaatggac aggatctgaa aatggactgc 840 aaggagtaca actatgacaa gagcattgtg gacagtggca ccaccaacct tcgtttgccc 900 aagaaagtgt ttgaagctgc agtcaaatcc atcaaggcag cctcctccac ggagaagttc 960 cctgatggtt tctggctagg agagcagctg gtgtgctggc aagcaggcac caccccttgg 1020 aacattttcc cagtcatctc actctaccta atgggtgagg ttacccagca gtccttccgc 1080 atcaccatcc ttccgcagca atacctgcgg ccagtggaag atgtggccac gtcccaagac 1140 gactgttaca agtttgccat ctcacagtca tccacgggca ctgttatggg agctgttatc 1200 atggagggct tctacgttgt ctttgatcgg gcccgaaaac gaattggctt tgctgtcagc 1260 gcttgccatg tgcacgatga gttcaggacg gcagcggtgg aaggcccttt tgtcaccttg 1320 gacatggaag actgtggcta caacattcca cagacagatg agtcacatca ccatcatcac 1380 cactaa 1386 4 461 PRT Homo sapiens 4 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Arg Arg Gly Ser Phe Val Glu 50 55 60 Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu 65 70 75 80 Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr 85 90 95 Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His 100 105 110 Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys 115 120 125 Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly 130 135 140 Thr Asp Leu Val Ser Ile Pro His Gly Pro Gln Val Thr Val Arg Ala 145 150 155 160 Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Gln Gly Ser 165 170 175 Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro 180 185 190 Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His 195 200 205 Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu 210 215 220 Gln Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly 225 230 235 240 Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile 245 250 255 Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn 260 265 270 Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser 275 280 285 Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe 290 295 300 Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe 305 310 315 320 Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly 325 330 335 Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly 340 345 350 Glu Val Thr Gln Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr 355 360 365 Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys 370 375 380 Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile 385 390 395 400 Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly 405 410 415 Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala 420 425 430 Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn 435 440 445 Ile Pro Gln Thr Asp Glu Ser His His His His His His 450 455 460 5 1368 DNA Homo sapiens 5 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg caagaagggc 180 agctttgtgg agatggtgga caacctgagg ggcaagtcgg ggcagggcta ctacgtggag 240 atgaccgtgg gcagcccccc gcagacgctc aacatcctgg tggatacagg cagcagtaac 300 tttgcagtgg gtgctgcccc ccaccccttc ctgcatcgct actaccagag gcagctgtcc 360 agcacatacc gggacctccg gaagggtgtg tatgtgccct acacccaggg caagtgggaa 420 ggggagctgg gcaccgacct ggtaagcatc ccccatggcc ccaacgtcac tgtgcgtgcc 480 aacattgctg ccatcactga atcagacaag ttcttcatca acggctccaa ctgggaaggc 540 atcctggggc tggcctatgc tgagattgcc aggcctgacg actccctgga gcctttcttt 600 gactctctgg taaagcagac ccacgttccc aacctcttct ccctgcagct ttgtggtgct 660 ggcttccccc tcaaccagtc tgaagtgctg gcctctgtcg gagggagcat gatcattgga 720 ggtatcgacc actcgctgta cacaggcagt ctctggtata cacccatccg gcgggagtgg 780 tattatgagg tgatcattgt gcgggtggag atcaatggac aggatctgaa aatggactgc 840 aaggagtaca actatgacaa gagcattgtg gacagtggca ccaccaacct tcgtttgccc 900 aagaaagtgt ttgaagctgc agtcaaatcc atcaaggcag cctcctccac ggagaagttc 960 cctgatggtt tctggctagg agagcagctg gtgtgctggc aagcaggcac caccccttgg 1020 aacattttcc cagtcatctc actctaccta atgggtgagg ttaccaacca gtccttccgc 1080 atcaccatcc ttccgcagca atacctgcgg ccagtggaag atgtggccac gtcccaagac 1140 gactgttaca agtttgccat ctcacagtca tccacgggca ctgttatggg agctgttatc 1200 atggagggct tctacgttgt ctttgatcgg gcccgaaaac gaattggctt tgctgtcagc 1260 gcttgccatg tgcacgatga gttcaggacg gcagcggtgg aaggcccttt tgtcaccttg 1320 gacatggaag actgtggcta caacattcca cagacagatg agtcataa 1368 6 455 PRT Homo sapiens 6 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Lys Lys Gly Ser Phe Val Glu 50 55 60 Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu 65 70 75 80 Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr 85 90 95 Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His 100 105 110 Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys 115 120 125 Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly 130 135 140 Thr Asp Leu Val Ser Ile Pro His Gly Pro Asn Val Thr Val Arg Ala 145 150 155 160 Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Asn Gly Ser 165 170 175 Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro 180 185 190 Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His 195 200 205 Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu 210 215 220 Asn Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly 225 230 235 240 Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile 245 250 255 Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn 260 265 270 Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser 275 280 285 Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe 290 295 300 Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe 305 310 315 320 Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly 325 330 335 Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly 340 345 350 Glu Val Thr Asn Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr 355 360 365 Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys 370 375 380 Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile 385 390 395 400 Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly 405 410 415 Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala 420 425 430 Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn 435 440 445 Ile Pro Gln Thr Asp Glu Ser 450 455 7 1368 DNA Homo sapiens 7 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg ccggaagggc 180 agctttgtgg agatggtgga caacctgagg ggcaagtcgg ggcagggcta ctacgtggag 240 atgaccgtgg gcagcccccc gcagacgctc aacatcctgg tggatacagg cagcagtaac 300 tttgcagtgg gtgctgcccc ccaccccttc ctgcatcgct actaccagag gcagctgtcc 360 agcacatacc gggacctccg gaagggtgtg tatgtgccct acacccaggg caagtgggaa 420 ggggagctgg gcaccgacct ggtaagcatc ccccatggcc ccaacgtcac tgtgcgtgcc 480 aacattgctg ccatcactga atcagacaag ttcttcatca acggctccaa ctgggaaggc 540 atcctggggc tggcctatgc tgagattgcc aggcctgacg actccctgga gcctttcttt 600 gactctctgg taaagcagac ccacgttccc aacctcttct ccctgcagct ttgtggtgct 660 ggcttccccc tcaaccagtc tgaagtgctg gcctctgtcg gagggagcat gatcattgga 720 ggtatcgacc actcgctgta cacaggcagt ctctggtata cacccatccg gcgggagtgg 780 tattatgagg tgatcattgt gcgggtggag atcaatggac aggatctgaa aatggactgc 840 aaggagtaca actatgacaa gagcattgtg gacagtggca ccaccaacct tcgtttgccc 900 aagaaagtgt ttgaagctgc agtcaaatcc atcaaggcag cctcctccac ggagaagttc 960 cctgatggtt tctggctagg agagcagctg gtgtgctggc aagcaggcac caccccttgg 1020 aacattttcc cagtcatctc actctaccta atgggtgagg ttaccaacca gtccttccgc 1080 atcaccatcc ttccgcagca atacctgcgg ccagtggaag atgtggccac gtcccaagac 1140 gactgttaca agtttgccat ctcacagtca tccacgggca ctgttatggg agctgttatc 1200 atggagggct tctacgttgt ctttgatcgg gcccgaaaac gaattggctt tgctgtcagc 1260 gcttgccatg tgcacgatga gttcaggacg gcagcggtgg aaggcccttt tgtcaccttg 1320 gacatggaag actgtggcta caacattcca cagacagatg agtcataa 1368 8 455 PRT Homo sapiens 8 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Arg Lys Gly Ser Phe Val Glu 50 55 60 Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu 65 70 75 80 Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr 85 90 95 Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His 100 105 110 Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys 115 120 125 Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly 130 135 140 Thr Asp Leu Val Ser Ile Pro His Gly Pro Asn Val Thr Val Arg Ala 145 150 155 160 Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Asn Gly Ser 165 170 175 Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro 180 185 190 Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His 195 200 205 Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu 210 215 220 Asn Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly 225 230 235 240 Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile 245 250 255 Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn 260 265 270 Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser 275 280 285 Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe 290 295 300 Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe 305 310 315 320 Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly 325 330 335 Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly 340 345 350 Glu Val Thr Asn Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr 355 360 365 Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys 370 375 380 Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile 385 390 395 400 Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly 405 410 415 Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala 420 425 430 Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn 435 440 445 Ile Pro Gln Thr Asp Glu Ser 450 455 9 1365 DNA Homo sapiens 9 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg caggggcagc 180 tttgtggaga tggtggacaa cctgaggggc aagtcggggc agggctacta cgtggagatg 240 accgtgggca gccccccgca gacgctcaac atcctggtgg atacaggcag cagtaacttt 300 gcagtgggtg ctgcccccca ccccttcctg catcgctact accagaggca gctgtccagc 360 acataccggg acctccggaa gggtgtgtat gtgccctaca cccagggcaa gtgggaaggg 420 gagctgggca ccgacctggt aagcatcccc catggcccca acgtcactgt gcgtgccaac 480 attgctgcca tcactgaatc agacaagttc ttcatcaacg gctccaactg ggaaggcatc 540 ctggggctgg cctatgctga gattgccagg cctgacgact ccctggagcc tttctttgac 600 tctctggtaa agcagaccca cgttcccaac ctcttctccc tgcagctttg tggtgctggc 660 ttccccctca accagtctga agtgctggcc tctgtcggag ggagcatgat cattggaggt 720 atcgaccact cgctgtacac aggcagtctc tggtatacac ccatccggcg ggagtggtat 780 tatgaggtga tcattgtgcg ggtggagatc aatggacagg atctgaaaat ggactgcaag 840 gagtacaact atgacaagag cattgtggac agtggcacca ccaaccttcg tttgcccaag 900 aaagtgtttg aagctgcagt caaatccatc aaggcagcct cctccacgga gaagttccct 960 gatggtttct ggctaggaga gcagctggtg tgctggcaag caggcaccac cccttggaac 1020 attttcccag tcatctcact ctacctaatg ggtgaggtta ccaaccagtc cttccgcatc 1080 accatccttc cgcagcaata cctgcggcca gtggaagatg tggccacgtc ccaagacgac 1140 tgttacaagt ttgccatctc acagtcatcc acgggcactg ttatgggagc tgttatcatg 1200 gagggcttct acgttgtctt tgatcgggcc cgaaaacgaa ttggctttgc tgtcagcgct 1260 tgccatgtgc acgatgagtt caggacggca gcggtggaag gcccttttgt caccttggac 1320 atggaagact gtggctacaa cattccacag acagatgagt cataa 1365 10 454 PRT Homo sapiens 10 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Arg Gly Ser Phe Val Glu Met 50 55 60 Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu Met 65 70 75 80 Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr Gly 85 90 95 Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His Arg 100 105 110 Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys Gly 115 120 125 Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly Thr 130 135 140 Asp Leu Val Ser Ile Pro His Gly Pro Asn Val Thr Val Arg Ala Asn 145 150 155 160 Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Asn Gly Ser Asn 165 170 175 Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro Asp 180 185 190 Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His Val 195 200 205 Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu Asn 210 215 220 Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly Gly 225 230 235 240 Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile Arg 245 250 255 Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn Gly 260 265 270 Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser Ile 275 280 285 Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe Glu 290 295 300 Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe Pro 305 310 315 320 Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly Thr 325 330 335 Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly Glu 340 345 350 Val Thr Asn Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr Leu 355 360 365 Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys Phe 370 375 380 Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile Met 385 390 395 400 Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly Phe 405 410 415 Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala Val 420 425 430 Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn Ile 435 440 445 Pro Gln Thr Asp Glu Ser 450 11 1386 DNA Homo sapiens 11 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg caagaagggc 180 agctttgtgg agatggtgga caacctgagg ggcaagtcgg ggcagggcta ctacgtggag 240 atgaccgtgg gcagcccccc gcagacgctc aacatcctgg tggatacagg cagcagtaac 300 tttgcagtgg gtgctgcccc ccaccccttc ctgcatcgct actaccagag gcagctgtcc 360 agcacatacc gggacctccg gaagggtgtg tatgtgccct acacccaggg caagtgggaa 420 ggggagctgg gcaccgacct ggtaagcatc ccccatggcc cccaggtcac tgtgcgtgcc 480 aacattgctg ccatcactga atcagacaag ttcttcatcc agggctccaa ctgggaaggc 540 atcctggggc tggcctatgc tgagattgcc aggcctgacg actccctgga gcctttcttt 600 gactctctgg taaagcagac ccacgttccc aacctcttct ccctgcagct ttgtggtgct 660 ggcttccccc tccagcagtc tgaagtgctg gcctctgtcg gagggagcat gatcattgga 720 ggtatcgacc actcgctgta cacaggcagt ctctggtata cacccatccg gcgggagtgg 780 tattatgagg tgatcattgt gcgggtggag atcaatggac aggatctgaa aatggactgc 840 aaggagtaca actatgacaa gagcattgtg gacagtggca ccaccaacct tcgtttgccc 900 aagaaagtgt ttgaagctgc agtcaaatcc atcaaggcag cctcctccac ggagaagttc 960 cctgatggtt tctggctagg agagcagctg gtgtgctggc aagcaggcac caccccttgg 1020 aacattttcc cagtcatctc actctaccta atgggtgagg ttacccagca gtccttccgc 1080 atcaccatcc ttccgcagca atacctgcgg ccagtggaag atgtggccac gtcccaagac 1140 gactgttaca agtttgccat ctcacagtca tccacgggca ctgttatggg agctgttatc 1200 atggagggct tctacgttgt ctttgatcgg gcccgaaaac gaattggctt tgctgtcagc 1260 gcttgccatg tgcacgatga gttcaggacg gcagcggtgg aaggcccttt tgtcaccttg 1320 gacatggaag actgtggcta caacattcca cagacagatg agtcacatca ccatcatcac 1380 cactaa 1386 12 461 PRT Homo sapiens 12 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Lys Lys Gly Ser Phe Val Glu 50 55 60 Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu 65 70 75 80 Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr 85 90 95 Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His 100 105 110 Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys 115 120 125 Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly 130 135 140 Thr Asp Leu Val Ser Ile Pro His Gly Pro Gln Val Thr Val Arg Ala 145 150 155 160 Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Gln Gly Ser 165 170 175 Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro 180 185 190 Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His 195 200 205 Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu 210 215 220 Gln Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly 225 230 235 240 Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile 245 250 255 Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn 260 265 270 Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser 275 280 285 Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe 290 295 300 Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe 305 310 315 320 Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly 325 330 335 Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly 340 345 350 Glu Val Thr Gln Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr 355 360 365 Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys 370 375 380 Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile 385 390 395 400 Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly 405 410 415 Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala 420 425 430 Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn 435 440 445 Ile Pro Gln Thr Asp Glu Ser His His His His His His 450 455 460 13 1368 DNA Homo sapiens 13 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg caagaagggc 180 agctttgtgg agatggtgga caacctgagg ggcaagtcgg ggcagggcta ctacgtggag 240 atgaccgtgg gcagcccccc gcagacgctc aacatcctgg tggatacagg cagcagtaac 300 tttgcagtgg gtgctgcccc ccaccccttc ctgcatcgct actaccagag gcagctgtcc 360 agcacatacc gggacctccg gaagggtgtg tatgtgccct acacccaggg caagtgggaa 420 ggggagctgg gcaccgacct ggtaagcatc ccccatggcc cccaggtcac tgtgcgtgcc 480 aacattgctg ccatcactga atcagacaag ttcttcatcc agggctccaa ctgggaaggc 540 atcctggggc tggcctatgc tgagattgcc aggcctgacg actccctgga gcctttcttt 600 gactctctgg taaagcagac ccacgttccc aacctcttct ccctgcagct ttgtggtgct 660 ggcttccccc tccagcagtc tgaagtgctg gcctctgtcg gagggagcat gatcattgga 720 ggtatcgacc actcgctgta cacaggcagt ctctggtata cacccatccg gcgggagtgg 780 tattatgagg tgatcattgt gcgggtggag atcaatggac aggatctgaa aatggactgc 840 aaggagtaca actatgacaa gagcattgtg gacagtggca ccaccaacct tcgtttgccc 900 aagaaagtgt ttgaagctgc agtcaaatcc atcaaggcag cctcctccac ggagaagttc 960 cctgatggtt tctggctagg agagcagctg gtgtgctggc aagcaggcac caccccttgg 1020 aacattttcc cagtcatctc actctaccta atgggtgagg ttacccagca gtccttccgc 1080 atcaccatcc ttccgcagca atacctgcgg ccagtggaag atgtggccac gtcccaagac 1140 gactgttaca agtttgccat ctcacagtca tccacgggca ctgttatggg agctgttatc 1200 atggagggct tctacgttgt ctttgatcgg gcccgaaaac gaattggctt tgctgtcagc 1260 gcttgccatg tgcacgatga gttcaggacg gcagcggtgg aaggcccttt tgtcaccttg 1320 gacatggaag actgtggcta caacattcca cagacagatg agtcatag 1368 14 455 PRT Homo sapiens 14 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Lys Lys Gly Ser Phe Val Glu 50 55 60 Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu 65 70 75 80 Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr 85 90 95 Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His 100 105 110 Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys 115 120 125 Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly 130 135 140 Thr Asp Leu Val Ser Ile Pro His Gly Pro Gln Val Thr Val Arg Ala 145 150 155 160 Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Gln Gly Ser 165 170 175 Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro 180 185 190 Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His 195 200 205 Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu 210 215 220 Gln Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly 225 230 235 240 Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile 245 250 255 Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn 260 265 270 Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser 275 280 285 Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe 290 295 300 Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe 305 310 315 320 Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly 325 330 335 Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly 340 345 350 Glu Val Thr Gln Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr 355 360 365 Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys 370 375 380 Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile 385 390 395 400 Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly 405 410 415 Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala 420 425 430 Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn 435 440 445 Ile Pro Gln Thr Asp Glu Ser 450 455 15 1386 DNA Homo sapiens 15 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg ccggaagggc 180 agctttgtgg agatggtgga caacctgagg ggcaagtcgg ggcagggcta ctacgtggag 240 atgaccgtgg gcagcccccc gcagacgctc aacatcctgg tggatacagg cagcagtaac 300 tttgcagtgg gtgctgcccc ccaccccttc ctgcatcgct actaccagag gcagctgtcc 360 agcacatacc gggacctccg gaagggtgtg tatgtgccct acacccaggg caagtgggaa 420 ggggagctgg gcaccgacct ggtaagcatc ccccatggcc cccaggtcac tgtgcgtgcc 480 aacattgctg ccatcactga atcagacaag ttcttcatcc agggctccaa ctgggaaggc 540 atcctggggc tggcctatgc tgagattgcc aggcctgacg actccctgga gcctttcttt 600 gactctctgg taaagcagac ccacgttccc aacctcttct ccctgcagct ttgtggtgct 660 ggcttccccc tccagcagtc tgaagtgctg gcctctgtcg gagggagcat gatcattgga 720 ggtatcgacc actcgctgta cacaggcagt ctctggtata cacccatccg gcgggagtgg 780 tattatgagg tgatcattgt gcgggtggag atcaatggac aggatctgaa aatggactgc 840 aaggagtaca actatgacaa gagcattgtg gacagtggca ccaccaacct tcgtttgccc 900 aagaaagtgt ttgaagctgc agtcaaatcc atcaaggcag cctcctccac ggagaagttc 960 cctgatggtt tctggctagg agagcagctg gtgtgctggc aagcaggcac caccccttgg 1020 aacattttcc cagtcatctc actctaccta atgggtgagg ttacccagca gtccttccgc 1080 atcaccatcc ttccgcagca atacctgcgg ccagtggaag atgtggccac gtcccaagac 1140 gactgttaca agtttgccat ctcacagtca tccacgggca ctgttatggg agctgttatc 1200 atggagggct tctacgttgt ctttgatcgg gcccgaaaac gaattggctt tgctgtcagc 1260 gcttgccatg tgcacgatga gttcaggacg gcagcggtgg aaggcccttt tgtcaccttg 1320 gacatggaag actgtggcta caacattcca cagacagatg agtcacatca ccatcatcac 1380 cactaa 1386 16 461 PRT Homo sapiens 16 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Arg Lys Gly Ser Phe Val Glu 50 55 60 Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu 65 70 75 80 Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr 85 90 95 Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His 100 105 110 Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys 115 120 125 Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly 130 135 140 Thr Asp Leu Val Ser Ile Pro His Gly Pro Gln Val Thr Val Arg Ala 145 150 155 160 Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Gln Gly Ser 165 170 175 Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro 180 185 190 Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His 195 200 205 Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu 210 215 220 Gln Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly 225 230 235 240 Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile 245 250 255 Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn 260 265 270 Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser 275 280 285 Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe 290 295 300 Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe 305 310 315 320 Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly 325 330 335 Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly 340 345 350 Glu Val Thr Gln Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr 355 360 365 Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys 370 375 380 Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile 385 390 395 400 Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly 405 410 415 Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala 420 425 430 Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn 435 440 445 Ile Pro Gln Thr Asp Glu Ser His His His His His His 450 455 460 17 1383 DNA Homo sapiens 17 atggctagca tgactggtgg acagcaaatg ggtcgcggat ccatggcggg agtgctgcct 60 gcccacggca cccagcacgg catccggctg cccctgcgca gcggcctggg gggcgccccc 120 ctggggctgc ggctgccccg ggagaccgac gaagagcccg aggagcccgg caggggcagc 180 tttgtggaga tggtggacaa cctgaggggc aagtcggggc agggctacta cgtggagatg 240 accgtgggca gccccccgca gacgctcaac atcctggtgg atacaggcag cagtaacttt 300 gcagtgggtg ctgcccccca ccccttcctg catcgctact accagaggca gctgtccagc 360 acataccggg acctccggaa gggtgtgtat gtgccctaca cccagggcaa gtgggaaggg 420 gagctgggca ccgacctggt aagcatcccc catggccccc aggtcactgt gcgtgccaac 480 attgctgcca tcactgaatc agacaagttc ttcatccagg gctccaactg ggaaggcatc 540 ctggggctgg cctatgctga gattgccagg cctgacgact ccctggagcc tttctttgac 600 tctctggtaa agcagaccca cgttcccaac ctcttctccc tgcagctttg tggtgctggc 660 ttccccctcc agcagtctga agtgctggcc tctgtcggag ggagcatgat cattggaggt 720 atcgaccact cgctgtacac aggcagtctc tggtatacac ccatccggcg ggagtggtat 780 tatgaggtga tcattgtgcg ggtggagatc aatggacagg atctgaaaat ggactgcaag 840 gagtacaact atgacaagag cattgtggac agtggcacca ccaaccttcg tttgcccaag 900 aaagtgtttg aagctgcagt caaatccatc aaggcagcct cctccacgga gaagttccct 960 gatggtttct ggctaggaga gcagctggtg tgctggcaag caggcaccac cccttggaac 1020 attttcccag tcatctcact ctacctaatg ggtgaggtta cccagcagtc cttccgcatc 1080 accatccttc cgcagcaata cctgcggcca gtggaagatg tggccacgtc ccaagacgac 1140 tgttacaagt ttgccatctc acagtcatcc acgggcactg ttatgggagc tgttatcatg 1200 gagggcttct acgttgtctt tgatcgggcc cgaaaacgaa ttggctttgc tgtcagcgct 1260 tgccatgtgc acgatgagtt caggacggca gcggtggaag gcccttttgt caccttggac 1320 atggaagact gtggctacaa cattccacag acagatgagt cacatcacca tcatcaccac 1380 taa 1383 18 460 PRT Homo sapiens 18 Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Gly Ser Met Ala 1 5 10 15 Gly Val Leu Pro Ala His Gly Thr Gln His Gly Ile Arg Leu Pro Leu 20 25 30 Arg Ser Gly Leu Gly Gly Ala Pro Leu Gly Leu Arg Leu Pro Arg Glu 35 40 45 Thr Asp Glu Glu Pro Glu Glu Pro Gly Arg Gly Ser Phe Val Glu Met 50 55 60 Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly Tyr Tyr Val Glu Met 65 70 75 80 Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile Leu Val Asp Thr Gly 85 90 95 Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His Pro Phe Leu His Arg 100 105 110 Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg Asp Leu Arg Lys Gly 115 120 125 Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu Gly Glu Leu Gly Thr 130 135 140 Asp Leu Val Ser Ile Pro His Gly Pro Gln Val Thr Val Arg Ala Asn 145 150 155 160 Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe Ile Gln Gly Ser Asn 165 170 175 Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu Ile Ala Arg Pro Asp 180 185 190 Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val Lys Gln Thr His Val 195 200 205 Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala Gly Phe Pro Leu Gln 210 215 220 Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser Met Ile Ile Gly Gly 225 230 235 240 Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp Tyr Thr Pro Ile Arg 245 250 255 Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg Val Glu Ile Asn Gly 260 265 270 Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn Tyr Asp Lys Ser Ile 275 280 285 Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro Lys Lys Val Phe Glu 290 295 300 Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser Thr Glu Lys Phe Pro 305 310 315 320 Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys Trp Gln Ala Gly Thr 325 330 335 Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu Tyr Leu Met Gly Glu 340 345 350 Val Thr Gln Gln Ser Phe Arg Ile Thr Ile Leu Pro Gln Gln Tyr Leu 355 360 365 Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp Asp Cys Tyr Lys Phe 370 375 380 Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met Gly Ala Val Ile Met 385 390 395 400 Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg Lys Arg Ile Gly Phe 405 410 415 Ala Val Ser Ala Cys His Val His Asp Glu Phe Arg Thr Ala Ala Val 420 425 430 Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp Cys Gly Tyr Asn Ile 435 440 445 Pro Gln Thr Asp Glu Ser His His His His His His 450 455 460 19 411 PRT Homo sapiens 19 Leu Pro Arg Glu Thr Asp Glu Glu Pro Glu Glu Pro Gly Lys Lys Gly 1 5 10 15 Ser Phe Val Glu Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly 20 25 30 Tyr Tyr Val Glu Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile 35 40 45 Leu Val Asp Thr Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His 50 55 60 Pro Phe Leu His Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg 65 70 75 80 Asp Leu Arg Lys Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu 85 90 95 Gly Glu Leu Gly Thr Asp Leu Val Ser Ile Pro His Gly Pro Asn Val 100 105 110 Thr Val Arg Ala Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe 115 120 125 Ile Asn Gly Ser Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu 130 135 140 Ile Ala Arg Pro Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val 145 150 155 160 Lys Gln Thr His Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala 165 170 175 Gly Phe Pro Leu Asn Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser 180 185 190 Met Ile Ile Gly Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp 195 200 205 Tyr Thr Pro Ile Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg 210 215 220 Val Glu Ile Asn Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn 225 230 235 240 Tyr Asp Lys Ser Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro 245 250 255 Lys Lys Val Phe Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser 260 265 270 Thr Glu Lys Phe Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys 275 280 285 Trp Gln Ala Gly Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu 290 295 300 Tyr Leu Met Gly Glu Val Thr Asn Gln Ser Phe Arg Ile Thr Ile Leu 305 310 315 320 Pro Gln Gln Tyr Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp 325 330 335 Asp Cys Tyr Lys Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met 340 345 350 Gly Ala Val Ile Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg 355 360 365 Lys Arg Ile Gly Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe 370 375 380 Arg Thr Ala Ala Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp 385 390 395 400 Cys Gly Tyr Asn Ile Pro Gln Thr Asp Glu Ser 405 410 20 411 PRT Homo sapiens 20 Leu Pro Arg Glu Thr Asp Glu Glu Pro Glu Glu Pro Gly Lys Lys Gly 1 5 10 15 Ser Phe Val Glu Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly 20 25 30 Tyr Tyr Val Glu Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile 35 40 45 Leu Val Asp Thr Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His 50 55 60 Pro Phe Leu His Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg 65 70 75 80 Asp Leu Arg Lys Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu 85 90 95 Gly Glu Leu Gly Thr Asp Leu Val Ser Ile Pro His Gly Pro Gln Val 100 105 110 Thr Val Arg Ala Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe 115 120 125 Ile Gln Gly Ser Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu 130 135 140 Ile Ala Arg Pro Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val 145 150 155 160 Lys Gln Thr His Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala 165 170 175 Gly Phe Pro Leu Gln Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser 180 185 190 Met Ile Ile Gly Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp 195 200 205 Tyr Thr Pro Ile Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg 210 215 220 Val Glu Ile Asn Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn 225 230 235 240 Tyr Asp Lys Ser Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro 245 250 255 Lys Lys Val Phe Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser 260 265 270 Thr Glu Lys Phe Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys 275 280 285 Trp Gln Ala Gly Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu 290 295 300 Tyr Leu Met Gly Glu Val Thr Gln Gln Ser Phe Arg Ile Thr Ile Leu 305 310 315 320 Pro Gln Gln Tyr Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp 325 330 335 Asp Cys Tyr Lys Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met 340 345 350 Gly Ala Val Ile Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg 355 360 365 Lys Arg Ile Gly Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe 370 375 380 Arg Thr Ala Ala Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp 385 390 395 400 Cys Gly Tyr Asn Ile Pro Gln Thr Asp Glu Ser 405 410 21 417 PRT Homo sapiens 21 Leu Pro Arg Glu Thr Asp Glu Glu Pro Glu Glu Pro Gly Lys Lys Gly 1 5 10 15 Ser Phe Val Glu Met Val Asp Asn Leu Arg Gly Lys Ser Gly Gln Gly 20 25 30 Tyr Tyr Val Glu Met Thr Val Gly Ser Pro Pro Gln Thr Leu Asn Ile 35 40 45 Leu Val Asp Thr Gly Ser Ser Asn Phe Ala Val Gly Ala Ala Pro His 50 55 60 Pro Phe Leu His Arg Tyr Tyr Gln Arg Gln Leu Ser Ser Thr Tyr Arg 65 70 75 80 Asp Leu Arg Lys Gly Val Tyr Val Pro Tyr Thr Gln Gly Lys Trp Glu 85 90 95 Gly Glu Leu Gly Thr Asp Leu Val Ser Ile Pro His Gly Pro Gln Val 100 105 110 Thr Val Arg Ala Asn Ile Ala Ala Ile Thr Glu Ser Asp Lys Phe Phe 115 120 125 Ile Gln Gly Ser Asn Trp Glu Gly Ile Leu Gly Leu Ala Tyr Ala Glu 130 135 140 Ile Ala Arg Pro Asp Asp Ser Leu Glu Pro Phe Phe Asp Ser Leu Val 145 150 155 160 Lys Gln Thr His Val Pro Asn Leu Phe Ser Leu Gln Leu Cys Gly Ala 165 170 175 Gly Phe Pro Leu Gln Gln Ser Glu Val Leu Ala Ser Val Gly Gly Ser 180 185 190 Met Ile Ile Gly Gly Ile Asp His Ser Leu Tyr Thr Gly Ser Leu Trp 195 200 205 Tyr Thr Pro Ile Arg Arg Glu Trp Tyr Tyr Glu Val Ile Ile Val Arg 210 215 220 Val Glu Ile Asn Gly Gln Asp Leu Lys Met Asp Cys Lys Glu Tyr Asn 225 230 235 240 Tyr Asp Lys Ser Ile Val Asp Ser Gly Thr Thr Asn Leu Arg Leu Pro 245 250 255 Lys Lys Val Phe Glu Ala Ala Val Lys Ser Ile Lys Ala Ala Ser Ser 260 265 270 Thr Glu Lys Phe Pro Asp Gly Phe Trp Leu Gly Glu Gln Leu Val Cys 275 280 285 Trp Gln Ala Gly Thr Thr Pro Trp Asn Ile Phe Pro Val Ile Ser Leu 290 295 300 Tyr Leu Met Gly Glu Val Thr Gln Gln Ser Phe Arg Ile Thr Ile Leu 305 310 315 320 Pro Gln Gln Tyr Leu Arg Pro Val Glu Asp Val Ala Thr Ser Gln Asp 325 330 335 Asp Cys Tyr Lys Phe Ala Ile Ser Gln Ser Ser Thr Gly Thr Val Met 340 345 350 Gly Ala Val Ile Met Glu Gly Phe Tyr Val Val Phe Asp Arg Ala Arg 355 360 365 Lys Arg Ile Gly Phe Ala Val Ser Ala Cys His Val His Asp Glu Phe 370 375 380 Arg Thr Ala Ala Val Glu Gly Pro Phe Val Thr Leu Asp Met Glu Asp 385 390 395 400 Cys Gly Tyr Asn Ile Pro Gln Thr Asp Glu Ser His His His His His 405 410 415 His 22 24 DNA Artificial Sequence Description of Artificial Sequence Primer 22 agctccctct cctgagaagc cacc 24 23 23 DNA Artificial Sequence Description of Artificial Sequence Primer 23 ccacaggtgc catctgtgtc tcc 23 24 22 DNA Artificial Sequence Description of Artificial Sequence Primer 24 caccagcacc acccagactt gg 22 25 22 DNA Artificial Sequence Description of Artificial Sequence Primer 25 aaccacggag gtgtggtcca gg 22 26 39 DNA Homo sapiens 26 cccgaggagc ccggcaagaa gggcagcttt gtggagatg 39 27 39 DNA Homo sapiens 27 catctccaca aagctgccct tcttgccggg ctcctcggg 39 28 40 DNA Homo sapiens 28 cccgaggagc ccggccggaa gggcagcttt gtggagatgg 40 29 40 DNA Homo sapiens 29 ccatctccac aaagctgccc ttccggccgg gctcctcggg 40 30 42 DNA Homo sapiens 30 cccgaggagc ccggcagggg cagctttgtg gagatggtgg ac 42 31 42 DNA Homo sapiens 31 gtccaccatc tccacaaagc tgcccctgcc gggctcctcg gg 42 32 39 DNA Homo sapiens 32 cccgaggagc ccggcaagaa gggcagcttt gtggagatg 39 33 39 DNA Homo sapiens 33 catctccaca aagctgccct tcttgccggg ctcctcggg 39 34 40 DNA Homo sapiens 34 cccgaggagc ccggccggaa gggcagcttt gtggagatgg 40 35 40 DNA Homo sapiens 35 ccatctccac aaagctgccc ttccggccgg gctcctcggg 40 36 42 DNA Homo sapiens 36 cccgaggagc ccggcagggg cagctttgtg gagatggtgg ac 42 37 42 DNA Homo sapiens 37 gtccaccatc tccacaaagc tgcccctgcc gggctcctcg gg 42 38 39 DNA Homo sapiens 38 cccgaggagc ccggcaagaa gggcagcttt gtggagatg 39 39 39 DNA Homo sapiens 39 catctccaca aagctgccct tcttgccggg ctcctcggg 39 40 40 DNA Homo sapiens 40 ccacagacag atgagtcatg acaccatcat caccactaag 40 41 40 DNA Homo sapiens 41 cttagtggtg atgatggtgt catgactcat ctgtctgtgg 40 42 6 PRT Artificial Sequence Description of Artificial Sequence 6-His tag 42 His His His His His His 1 5 43 29 DNA Artificial Sequence Description of Artificial Sequence Primer 43 cgggatccat ggcgggagtg ctgcctgcc 29 44 40 DNA Artificial Sequence Description of Artificial Sequence Primer 44 cgggatcctt atgactcatc tgtctgtgga atgttgtagc 40 45 18 DNA Artificial Sequence Description of Artificial Sequence His tag oligonucleotide sequence 45 catcaccatc atcaccac 18 46 12 PRT Artificial Sequence Description of Artificial Sequence Illustrative synthetic flourescent peptide 46 Arg Glu Glu Val Asn Leu Asp Ala Glu Phe Lys Arg 1 5 10 

1. A BACE protein, which comprises the sequence set out in residues 45 to 455 of SEQ ID NO:2 (43 to 453 SwissProt P56817), or a fragment thereof comprising residues corresponding to 58 to 398 of SEQ ID NO:2, modified by the following changes: substitution or deletion of at least one residue which is a proteolytic cleavage site, recognised by clostripain; and optionally the replacement of from 1 to 30 other amino acids by an equivalent or fewer number of amino acids.
 2. A protein according to claim 1 wherein at least one of residues 44, 47, 57, 58 and 59 of SEQ ID NO:2 are substituted.
 3. A protein according to claim 1 wherein residues 58 and/or 59 are lysine.
 4. A protein according to claim 1 wherein the asparagine residues at positions 155, 174, 225 and 356 (SwissProt P56817 153, 172, 223 and 354) are replaced by glutamine residues.
 5. A protein according to claim 1 wherein the fragment is truncated at the C-terminus such that at least residues 449 et seq. of SEQ ID NO:2 are absent.
 6. A method of making a truncated BACE protein, which method comprises proteolytically cleaving the protein of claim
 1. 7. The method of claim 6 wherein said cleavage is at and includes one or more of residues 44, 47, 57, 58 and
 59. 8. A BACE protein obtained or obtainable by the method of claim
 7. 9. A protein according to claim 8 wherein the N-terminal is residue 45 of SEQ ID NO:2.
 10. A protein according to claim 1 which is selected from: (a) SEQ ID 6; (b) SEQ ID 8; (c) SEQ ID 10; (d) SEQ ID 12; (e) SEQ ID 14; (f) SEQ ID 16; (g) SEQ ID 18; or a truncated BACE protein obtainable by a method comprising proteolytically cleaving the protein of claim 1, wherein said cleavage is at and includes one or more of residues 44, 47, 57, 58, and 59, wherein the protein is selected from (h) SEQ ID 19; (i) SEQ ID 20; (j) SEQ ID
 21. 11. A nucleic acid encoding the protein of claim
 1. 12. A vector comprising the nucleic acid of claim
 11. 13. A host cell comprising the vector of claim
 12. 14. A process for producing the protein of claim 1 comprising the steps of: (a) culturing a host cell comprising a vector comprising a nucleic acid encoding the protein of claim 1 under conditions suitable for expression of the protein; and optionally (b) isolating the expressed recombinant BACE protein.
 15. A process for producing refolded recombinant BACE protein comprising the steps of: (a) solubilising the recombinant BACE; (b) diluting the solubilised BACE into an aqueous buffer containing 10 to 50 mM sulfobetaine; and (c) maintaining the diluted solution at low temperature and at high pH for at least 2 weeks.
 16. A process for producing a crystal of BACE comprising the step of refolding recombinant BACE protein according to the process of claim
 14. 17. A process for producing a crystal of a BACE protein comprising the step of growing the crystal by vapour diffusion using a reservoir buffer that contains 18-26% PEG 5000 MME, 180-220 mM ammonium iodide and 180-220 mM tri-sodium citrate pH 6.4-6.6, and optionally 0-5% glycerol.
 18. A process according to claim 15 wherein the BACE protein is human BACE.
 19. A process according to claim 17 wherein the BACE protein is human BACE.
 20. A process according to claim 15 wherein the BACE protein is as defined in claim
 1. 21. A process according to claim 17 wherein the BACE protein is as defined in claim
 1. 22. A crystal of a BACE protein having a hexagonal space group P6₁22.
 23. The crystal of claim 22 having unit cell dimensions of a=b=103.2 Å, c=169.1 Å, α=β=60°, γ=120°, and a unit cell variability of 5% in all dimensions.
 24. A crystal of a BACE protein comprising a structure defined by all or a portion of the co-ordinates of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å.
 25. A crystal of the protein of claim
 1. 26. The crystal of claim 22 having a resolution better than 2.5 Å.
 27. The crystal of claim 24 having a resolution better than 2.5 Å.
 28. The crystal of claim 22 which is soaked with one or more compound(s) to form co-complex structures.
 29. The crystal of claim 24 which is soaked with one or more compound(s) to form co-complex structures.
 30. The crystal of claim 22 wherein the BACE is co-crystallized with one or more compound(s) to form co-crystallized structures.
 31. The crystal of claim 24 wherein the BACE is co-crystallized with one or more compound(s) to form co-crystallized structures.
 32. The crystal of claim 22 which is an apo crystal.
 33. The crystal of claim 24 which is an apo crystal.
 34. A computer-based method for the analysis of the interaction of a molecular structure with a PACE protein, which comprises: (a) providing a structure comprising a three-dimensional representation of PACE or of a portion of BACE, which representation comprises all or a portion of the coordinates of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å. (b) providing a molecular structure to be fitted to said BACE structure; and (c) fitting the molecular structure to the PACE structure of (a).
 35. The method of claim 34 wherein the molecular structure to be fitted is in the form of a model of a pharmacophore.
 36. The method of claim 34 wherein the three-dimensional representation is a model constructed from all or a portion of the coordinates of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å.
 37. The method of claim 36 wherein the model is: (a) a wire-frame model; (b) a chicken-wire model; (c) a ball-and-stick model; (d) a space-filling model; (e) a stick-model; (f) a ribbon model; (g) a snake model; (h) an arrow and cylinder model; (i) an electron density map; (j) a molecular surface model.
 38. A computer-based method for the analysis of molecular structures which comprises: (a) providing the coordinates of at least two atoms of a PACE structure as defined in Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å (“selected coordinates”); (b) providing the structure of a molecular structure to be fitted to the selected coordinates; and (c) fitting the structure to the selected coordinates of the BACE structure.
 39. The method of claim 38 wherein the selected coordinates are of at least 5, 10, 50, 100 or 500 atoms.
 40. The method of claim 34 wherein the coordinates of Table 1 represent a binding pocket.
 41. The method of claim 38 wherein the coordinates of Table 1 represent a binding pocket.
 42. The method of claim 40 wherein the coordinates of Table 1 comprise those relating to residues SER71, GLY72, LEU91, ASP93, GLY95, SER96, VAL130, PRO131, TYR132, THR133, GLN134, ILE171, ILE179, ILE187, ALA188, ARG189, PRO190, TRP258, TYR259, ASP284, LYS285, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and ARG368 (based on the numbering of SwissProt P56817).
 43. The method of claim 41 wherein the coordinates of Table 1 comprise those relating to residues SER71, GLY72, LEU91, ASP93, GLY95, SER96, VAL130, PRO131, TYR132, THR133, GLN134, ILE171, ILE179, ILE187, ALA188, ARG189, PRO190, TRP258, TYR259, ASP284, LYS285, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and ARG368 (based on the numbering of SwissProt P56817).
 44. A computer-based method of rational drug design comprising the method of claim
 28. 45. A computer-based method of rational drug design comprising the method of claim
 38. 46. A computer-based method of rational drug design comprising comprising: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å (“selected coordinates”); (b) providing the structures of a plurality of molecular fragments; (c) fitting the structure of each of the molecular fragments to the selected coordinates; and (d) assembling the molecular fragments into a single molecule to form a candidate modulator molecule.
 47. A method for identifying a candidate modulator of BACE comprising the steps of: (a) employing a three-dimensional structure of BACE, at least one sub-domain thereof, or a plurality of atoms thereof, to characterise at least one BACE binding cavity, the three-dimensional structure being defined by atomic coordinate data according to Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å; and (b) identifying the candidate modulator by designing or selecting a compound for interaction with the binding cavity.
 48. The method of claim 34 further comprising the step, of: (a) obtaining or synthesising the molecular structure or modulator; and (b) contacting the molecular structure or modulator with BACE to determine the ability of the molecular structure or modulator to interact with BACE.
 49. The method of claim,38 further comprising the step of: (a) obtaining or synthesising the molecular structure or modulator; and (b) contacting the molecular structure or modulator with BACE to determine the ability of the molecular structure or modulator to interact with BACE.
 50. The method of claim 46 further comprising the step of: (a) obtaining or synthesising the molecular structure or modulator; and (b) contacting the molecular structure or modulator with BACE to determine the ability of the molecular structure or modulator to interact with BACE.
 51. The method of claim 47 further comprising the step of:. (a) obtaining or synthesising the molecular structure or modulator; and (b) contacting the molecular structure or modulator with BACE to determine the ability of the molecular structure or modulator to interact with BACE.
 52. A method of assessing the ability of a candidate modulator to interact with BACE which comprises the steps of: (a) obtaining or synthesising said candidate modulator; (b) forming a crystallized complex of a BACE protein of claim 1 and said candidate modulator; and (c) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said candidate modulator to interact with BACE.
 53. A method for determining the structure of a compound bound to BACE, said method comprising: (a) mixing BACE with the compound to form a BACE-compound complex; (b) crystallizing the BACE-compound complex; and (c) determining the structure of said BACE-compound(s) complex by reference to the data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å.
 54. A method for determining the structure of a compound bound to BACE, said method comprising: (a) providing a crystal of BACE; (b) soaking the crystal with one or more compound(s) to form a complex; and (c) determining the structure of the complex by employing the data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å.
 55. A method of determining the three dimensional structure of a BACE homologue or analogue of unknown structure, the method comprising the steps of: (a) aligning a representation of an amino acid sequence of the BACE homologue or analogue with the amino acid sequence of the BACE of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å to match homologous regions of the amino acid sequences; (b) modelling the structure of the matched homologous regions of said target BACE of unknown structure on the corresponding regions of the BACE structure as defined by Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å; and (c) determining a conformation for the BACE homologue or analogue which substantially preserves the structure of said matched homologous regions.
 56. A method of providing data for generating structures and/or performing rational drug design for BACE, BACE homologues or analogues, complexes of BACE with a potential modulator, or complexes of BACE homologues or analogues with potential modulators, the method comprising (i) establishing communication with a remote device containing computer-readable data comprising at least one of: (a) atomic coordinate data according to Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å, said data defining the three-dimensional structure of BACE, at least one sub-domain of the three-dimensional structure of BACE, or the coordinates of a plurality of atoms of BACE; (b) structure factor data for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å. (c) atomic coordinate data of a target BACE homologue or analogue generated by homology modelling of the target based on the data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å. (d) atomic coordinate data of a protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5Å; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d); and (ii) receiving said computer-readable data from said remote device.
 57. A computer system containing one or more of: (a) atomic coordinate data according to Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å, said data defining the three-dimensional structure of BACE or at least selected coordinates thereof; (b) structure factor data (where a structure factor comprises the amplitude and phase of the diffracted wave) for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å; (d) atomic coordinate data of a target BACE protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å; or (e) structure factor data derivable from the atomic coordinate data of (c) or (d).
 58. The computer system of claim 57 comprising: a computer-readable data storage medium comprising data storage material encoded with the computer-readable data; (a) a working memory for storing instructions for processing said computer-readable data; and (b) a central-processing unit coupled to said working memory and to said computer-readable data storage medium for processing said computer-readable data and thereby generating structures and/or performing rational drug design.
 59. A method for determining the structure of a protein, which method comprises: providing the co-ordinates of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å, and either (a) positioning the co-ordinates in the crystal unit cell of said protein so as to provide a structure for said protein or (b) assigning NMR spectra Peaks of said protein by manipulating the coordinates of Table 1±a root mean square deviation from the Cα atoms of less than 0.5 Å.
 60. A method of preparing a composition comprising identifying a molecular structure or modulator according to the method of claim 34, and admixing the molecule with a carrier.
 61. A method of preparing a composition comprising identifying a molecular structure or modulator according to the method of claim 38, and admixing the molecule with a carrier.
 62. A method of preparing a composition comprising identifying a molecular structure or modulator according to the method of claim 46, and admixing the molecule with a carrier.
 63. A method of preparing a composition comprising identifying a molecular structure or modulator according to the method of claim 47, and admixing the molecule with a carrier.
 64. A method of preparing a composition comprising identifying a molecular structure or modulator according to the method of claim 52, and admixing the molecule with a carrier.
 65. A process for producing a medicament, pharmaceutical composition or drug, the process comprising: (a) identifying a molecular structure or modulator according to the method as defined claim 34; and (b) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 66. A process for producing a medicament, pharmaceutical composition or drug, the process comprising: (a) identifying a molecular structure or modulator according to the method as defined claim 38; and (b) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 67. A process for producing a medicament, pharmaceutical composition or drug, the process comprising: (a),identifying a molecular structure or modulator according to the method as defined claim 46; and (b) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 68. A process for producing a medicament, pharmaceutical composition or drug, the process comprising: (a) identifying a molecular structure or modulator according to the method as defined claim 47; and (b) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 69. A process for producing a medicament, pharmaceutical composition or drug, the process comprising: (a) identifying a molecular structure or modulator according to the method as defined claim 52; and (b) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 70. A process according to claim 65 which further comprises optimising the structure of the modulator molecule; and preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 71. A process according to claim 66 which further comprises optimising the structure of the modulator molecule; and preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 72. A process according to claim 67 which further comprises optimising the structure of the modulator molecule; and preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 73. A process according to claim 68 which further comprises optimising the structure of the modulator molecule; and preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 74. A process according to claim 69 which further comprises optimising the structure of the modulator molecule; and preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.
 75. A compound identified, produced or obtainable by the process or method of claim
 34. 76. A compound identified, produced or obtainable by the process or method of claim
 38. 77. A compound identified, produced or obtainable by the process or method of claim
 46. 78. A compound identified, produced or obtainable by the process or method of claim
 47. 79. A compound identified, produced or obtainable by the process or method of claim
 52. 80. A compound of claim 75 or composition thereof for use in medicine.
 81. A compound of claim 76 or composition thereof for use in medicine.
 82. A compound of claim 77 or composition thereof for use in medicine.
 83. A compound of claim 78 or composition thereof for use in medicine.
 84. A compound of claim 79 or composition thereof for use in medicine. 